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Neurogenic lower urinary tract dysfunction (NLUTD), stemming from neurodegenerative diseases or injuries such as cerebrovascular accidents, spinal cord injuries, and Alzheimer's disease, significantly impacts quality of life. Symptoms, including urinary frequency, urgency, incontinence, and retention, are managed with devices ranging from catheters to sacral neuromodulation. This Neurogenic Bladder Research Group (NBRG) report explores the intersection between clinical, basic science, and engineering research in personalized NLUTD treatment, identifies critical gaps for future investigation, and examines how interdisciplinary collaboration can drive engineering solutions to improve care. In December 2024, NBRG convened its annual meeting, gathering experts from engineering, clinical practice, research, and patient advocacy to discuss challenges in NLUTD research and explore collaborative solutions. Enhanced collaboration between clinicians and engineers offers promise for improving NLUTD care. Clinicians provide critical insight into patient needs but often lack time for sustained research, while engineers contribute technical innovation yet may lack clinical exposure. Integrating patient perspectives emerged as a key theme, ensuring that technologies are practical, acceptable, and aligned with end-user needs. Discussions emphasized expanding programs that support cross-disciplinary, multi-institutional research and identifying funding pathways tailored to interdisciplinary efforts. Strategies to enhance patient involvement and foster inclusive research that reflects patient diversity and socio-demographic factors influencing care were also discussed. Institutional support, interdisciplinary collaboration, and the active engagement of patients are key to advancing clinical care and NLUTD treatments.
Alzheimer's disease(AD) is a neurodegenerative disorder characterized by progressive cognitive decline. Current treatment strategies mainly focus on symptomatic regulation of the neurotransmitter system, but their intervention effects on key pathological processes such as amyloid β(Aβ) deposition and abnormal phosphorylation of Tau protein remain limited. Therefore, it is urgent to explore new intervention targets from the perspective of the key mechanisms underlying the disease's occurrence and development. In recent years, mitochondrial dysfunction and imbalanced mitophagy have been recognized as closely related to the onset and progression of AD. The PTEN-induced putative kinase 1(PINK1)/E3 ubiquitin-protein ligase parkin(Parkin) pathway is a classic mechanism for the recognition, ubiquitination marking, and autophagic clearance of damaged mitochondria. Multiple studies have shown that under AD pathological conditions, the expression of this pathway is blocked, or its activity is reduced, leading to restricted mitophagy flux and obstacle clearance, which in turn exacerbate oxidative stress, energy metabolism disorders, and synaptic function damage, accelerating neuronal degeneration. Based on this, intervention strategies targeting PINK1/Parkin-mediated mitophagy have gradually attracted attention. Existing research indicates that single components and formulas of TCM, as well as some bioactive molecules, can reduce Aβ deposition, inhibit abnormal phosphorylation of Tau protein, and enhance synaptic plasticity by regulating PINK1/Parkin-mediated mitophagy, thereby exerting neuroprotective effects and improving cognitive function. However, the current evidence mainly comes from experimental studies, and the blood-brain barrier permeability, long-term safety, and clinical reproducibility of these interventions still need further verification. This article systematically reviewed the molecular mechanisms and upstream regulatory networks of PINK1/Parkin-mediated mitophagy, elaborated on the research evidence of its role in the pathological process of AD, and focused on summarizing the research progress of TCM interventions targeting this pathway, aiming to provide references for subsequent mechanism verification, evidence-based research design, and exploration of comprehensive intervention strategies.
Alzheimer's disease (AD) remains a major global health crisis due to its complex pathophysiology and limited therapeutic effectiveness. Despite advances in understanding key mechanisms such as amyloid-beta accumulation, tau pathology and neuroinflammation, current therapies provide limited clinical benefit. Multiple factors contribute to limitations and highlight the difficulty of translating scientific advancements into meaningful improvement in patient outcomes. This article provides a comprehensive and critical review of therapeutic, biological, clinical, and systemic barriers to effective Alzheimer's disease management as well as showcasing emerging strategies aimed to improve early detection, treatment approaches, and overall disease prevention.
Spermidine is a naturally occurring polyamine involved in multiple cellular processes, including growth regulation, protein translation, and autophagy. Increasing attention has been devoted to its potential neuroprotective effects, particularly in Alzheimer's disease (AD), a neurodegenerative disorder characterized by β-amyloid and phosphorylated tau accumulation, synaptic dysfunction, and progressive neuronal loss. In this narrative review, we examine potential mechanisms through which spermidine may influence AD pathophysiology and summarize available preclinical and clinical evidence. Preclinical studies indicate that spermidine induces autophagy, a key cellular clearance pathway responsible for removing damaged organelles and aggregated proteins. Because impaired neuronal autophagy contributes to the accumulation of β-amyloid and tau in AD, increasing intracellular spermidine levels may enhance the degradation of these toxic species. In addition, spermidine exhibits anti-inflammatory and antioxidant properties, attenuates microglial activation, and supports mitochondrial function. In animal models of AD and brain aging, spermidine administration has been associated with improvements in cognitive performance and synaptic function. However, human clinical evidence remains limited and largely inconclusive. Observational studies suggest associations between higher dietary spermidine intake and better cognitive outcomes, but do not establish causality. Randomized clinical trials to date are few, include small and heterogeneous populations, and have not demonstrated consistent effects on primary cognitive endpoints. Overall, spermidine represents a biologically plausible modulator of pathways relevant to neurodegeneration, but translation of preclinical findings into clinical benefit remains uncertain. Current evidence is insufficient to support its use as a therapeutic or preventive intervention in AD, and further well-designed clinical studies are required to clarify its efficacy and mechanisms of action. Alzheimer’s disease is one of the most common causes of memory loss in older adults. Researchers are searching for ways to protect brain cells and slow the biological processes that lead to this disease. One molecule that has recently attracted attention is spermidine, a natural compound found in all living cells and in many foods, including whole grains, legumes, mushrooms, and aged cheeses. Spermidine plays several roles in the body. One of its most important effects is activation of autophagy, a natural cellular process that removes damaged proteins and other cellular waste. This process is relevant to Alzheimer’s disease because the condition is associated with the accumulation of abnormal proteins in the brain. Experimental studies also suggest that spermidine may influence inflammation in the brain, support mitochondrial function (the energy system of cells), and help maintain communication between nerve cells. In this review, we summarized evidence from laboratory experiments, animal studies, and available human research. In animal models of brain aging and Alzheimer’s disease, spermidine consistently shows neuroprotective effects and can improve memory performance. Human evidence is more limited. Observational studies suggest that higher dietary spermidine intake may be associated with better cognitive performance, while clinical trials investigating supplementation have produced mixed results. Spermidine is naturally present in many foods and is increasingly studied in the context of aging and brain health. Overall, current evidence suggests that spermidine may play a role in brain aging. Larger and well-designed clinical studies are needed to clarify its potential relevance for Alzheimer’s disease.
Alzheimer's disease (AD) is characterized by dysfunction in multiple cognitive domains. Patients with AD demonstrate a relative attenuation and dysregulation of theta and gamma oscillations in the temporal and parietal lobes at an early stage. Transcranial alternating current stimulation (tACS) has been shown to modulate neural oscillations in different regions of the brain, affecting higher cognitive functions such as motor function, memory, and learning. To observe the clinical efficacy and after-effects of biparietal 40 Hz tACS in treating AD patients, to analyze its safety and feasibility, and to deeply explore the effects of tACS on time-varying brain networks and dynamic functional connectivity. In the study, patients with mild AD who were treated in the First Hospital of Hebei Medical University from October 2022 to August 2023 were recruited, randomly divided into tACS group or Sham group, and then respectively received either biparietal 40 Hz tACS or sham stimulation for 15 consecutive days, each lasting 30 min. Neuropsychological assessment scales were collected to assess the efficacy at three time points: pre-stimulation, post-stimulation, and 10-week follow-up. Additionally, transcranial magnetic stimulation with electroencephalography (TMS-EEG) and functional magnetic resonance imaging (fMRI) were collected to explore time-varying brain networks and functional connectivity. Patients with AD exhibited improvements in global cognition, memory, language, attention, and executive functions following tACS treatment compared with those before treatment. Additionally, the neuropsychiatric inventory scores were decreased significantly after tACS treatment. The clinical efficacies were not obvious in Sham group. These results indicated that tACS treatment had significant short-term efficacy and good stability. The brain time-varying EEG network patterns were analyzed using the adaptive directed transfer function. The analysis showed enhanced information flows from the temporal and prefrontal regions and from the posterior to anterior regions after tACS treatment. In contrast, decreased information flow was observed from the left to right frontal regions. The fMRI analysis revealed enhanced connectivity within default mode network and between default mode network and Frontoparietal network after active treatment. The 40 Hz biparietal tACS is a potentially safe and effective treatment for AD with certain long-term efficacy by modulating dynamic functional connectivity. The trial was retrospectively registered at the Chinese Clinical Trial Registry (registration number: ChiCTR2500115019).
As a key mechanosensitive ion channel, Piezo1 plays a critical role in various brain functions, including the regulation of cerebral blood flow and neuronal excitability, by converting mechanical stimuli into biochemical signals. This study conducted a quantitative and visual analysis of the global research landscape, evolving trends, and knowledge structure of Piezo1 in brain research from 2014 to 2025. A comprehensive bibliometric analysis was conducted. We conducted a comprehensive literature search in the Web of Science and Scopus databases for publications focusing on Piezo1 in the brain from January 1, 2014, to October 1, 2025. After rigorous screening and deduplication, 173 studies were finally included in the analysis. Scientometric indicators and visualization tools were employed to examine publication trends, core journals, productive authors and countries, and keyword co-occurrence networks. Annual publication output in this field increased rapidly, with an average growth rate of 34.48%. Research publications are concentrated in a limited number of high-impact journals, reflecting a strong academic focus. Keyword analysis identified core research hotspots, including "mechanotransduction," "ion channels," and "neuroinflammation," highlighting the pivotal role of Piezo1 in cerebral hemodynamics and neuropathology. Intellectual structure analysis revealed that foundational mechanistic studies dominate the current literature. Although basic research on Piezo1 in the brain has advanced significantly, studies directly targeting its clinical translation are limited. These findings highlight a clear knowledge gap between mechanistic understanding and therapeutic applications. Future research should prioritize bridging this gap by fostering interdisciplinary collaborations that translate fundamental insights into clinical validation, thereby accelerating the development of Piezo1 as a novel therapeutic target for neurological disorders.
The blood-brain barrier (BBB) is a major obstacle to targeted drug delivery for central nervous system (CNS) diseases. Although liposomes and polymeric nanoparticles have improved brain drug delivery, limitations remain in BBB targeting, long-term biocompatibility, and in vivo clearance. Exosomes are endogenous nanoscale extracellular vesicles with favourable biocompatibility, low immunogenicity, and BBB-crossing potential. Therefore, this bibliometric study summarises the current research status, future research trends, and challenges in the more specific field of exosome-mediated BBB drug delivery. A comprehensive search was conducted across the Web of Science Core Collection (WoSCC), PubMed, and Embase databases for relevant English-language literature on exosome-mediated drug delivery across the blood-brain barrier from 2015 to 2025. WoSCC served as the primary source for bibliometric analysis. PubMed and Embase databases were used for supplementary validation. Software such as VOSviewer, CiteSpace, and R-bibliometrix was employed for literature visualisation analysis. This study included 1,365 relevant articles from the WoSCC database, and the annual publication volume showed a steady upward trend. China and the United States significantly lead in both the number of publications and the number of core contributing institutions in this field. Co-occurrence analysis of keywords showed that research hotspots are mainly focused on exosomes, the blood-brain barrier, drug delivery, and Alzheimer's disease. PubMed and Embase were used as supplementary validation databases, including 1,089 and 1,517 records, respectively. Their annual publication trends, major countries/regions, core journals, and keywords/themes were generally consistent with WoSCC, supporting the macro-level stability of the bibliometric findings. Unlike previous bibliometric analyses that mainly focused on overall trends in CNS exosome research, this study focuses specifically on the direction of exosome-mediated drug delivery across the BBB. The findings show a shift from basic vesicle characterisation toward engineered delivery systems, CNS disease applications, and translational evaluation. Mammalian-derived exosomes remain dominant, while plant-derived vesicles, AI-assisted design, biomimetic hybrid nanovesicles, and gut-brain axis strategies are emerging areas of focus. Future research should prioritise systematic platform comparisons, standardised evaluation, quality control, scalable production, long-term safety, and regulatory pathways.
This study aimed to systematically characterize the global research landscape, collaboration patterns, knowledge structure, and emerging hotspots of glucagon-like peptide-1 receptor agonists in neurodegenerative diseases using bibliometric methods. Publications related to glucagon-like peptide-1 receptor agonists and neurodegenerative diseases were retrieved from the Web of Science Core Collection from 2006 to 2025. Only English-language articles and reviews were included. Bibliometric analyses were performed using Bibliometrix, VOSviewer, and CiteSpace to evaluate annual publication trends, country and institutional contributions, author collaborations, journal distribution, citation structures, keyword co-occurrence, thematic evolution, and citation bursts. A Scopus-based sensitivity analysis was conducted to assess the robustness of the main bibliometric findings. A total of 1,202 publications were included, with annual output increasing from 2 in 2006 to 241 in 2025, particularly after 2020. China, the USA, and England were the leading contributors and major collaboration hubs. Shanxi Medical University, Lancaster University, and the National Institute on Aging were among the most productive institutions, while major journals included International Journal of Molecular Sciences, Neuropharmacology, European Journal of Pharmacology, Frontiers in Endocrinology, Frontiers in Pharmacology, and Journal of Alzheimer's Disease. Keyword and citation analyses indicated a thematic shift from exendin-4, Alzheimer's disease, Parkinson's disease, and neuroprotection toward semaglutide, neuroinflammation, cognitive impairment, clinical efficacy, evidence synthesis, and combination therapy. Research on glucagon-like peptide-1 receptor agonists in neurodegenerative diseases has expanded rapidly over the past two decades. Current bibliometric evidence suggests that this field has evolved from preclinical exploration toward broader translational and clinical research, with increasing attention to neuroinflammation, metabolic dysfunction, cognitive outcomes, and newer incretin-based therapies. However, the therapeutic implications of glucagon-like peptide-1 receptor agonists for neurodegenerative diseases remain to be further validated by high-quality mechanistic studies and well-designed clinical trials.
Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and functional impairment, posing significant challenges for early detection and management. In recent years, digital health technologies have emerged as promising tools to enhance the diagnosis, monitoring, and treatment of AD. This review paper explores the multifaceted role of digital health technologies in the early detection and management of Alzheimer's disease. We examine the use of wearable devices that monitor cognitive function and daily activities, as well as mobile health applications designed for cognitive training and symptom tracking. Additionally, we analyze the impact of telehealth services in providing remote care, particularly for underserved populations. The integration of artificial intelligence and machine learning for analyzing behavioral and cognitive data to support early diagnosis and risk assessment is also discussed. Furthermore, we explore the concept of digital biomarkers and their potential to complement traditional diagnostic methods. Ethical considerations surrounding privacy, data security, and informed consent are addressed to ensure responsible implementation of these technologies. Finally, we highlight gaps in current research and propose future directions for integrating digital health technologies into Alzheimer's care, emphasizing the potential for personalized interventions tailored to individual patient needs. This review underscores the transformative potential of digital health to reshape Alzheimer's disease management and improve patient outcomes.
The publisher identified that references 42 and 43 were duplicated in the published version of this article [1]. The error has now been corrected. The original article can be found online at: https://www.benthamscience.com/article/150567 Details of the error and the correction are provided below: Original: [42] Muksimova S, Umirzakova S, Iskhakova N, Khaitov A, Cho YI. Advanced convolutional neural network with attention mechanism for Alzheimer's disease classification using MRI. Comput Biol Med 2025; 190, 110095. [43] Muksimova S, Umirzakova S, Iskhakova N, Khaitov A, Cho YI. Advanced convolutional neural network with attention mechanism for Alzheimer's disease classification using MRI. Comput Biol Med 2025; 190: 110095. http://dx.doi.org/10.1016/j.compbiomed.2025.110095 PMID: 40158456 Corrected: [42] Muksimova S, Umirzakova S, Iskhakova N, Khaitov A, Cho YI. Advanced convolutional neural network with attention mechanism for Alzheimer's disease classification using MRI. Comput Biol Med 2025; 190, 110095. http://dx.doi.org/10.1016/j.compbiomed.2025.110095 PMID: 40158456 [43] Olaimat MA, Bozdag S, Saeed F. TA-RNN: An attention-based time-aware recurrent neural network architecture to predict progression of Alzheimer's disease. Alzheimer's Dement 2024; 20(S1).
Single-cell sequencing and multi-omics technologies are revolutionizing research on central nervous system (CNS) diseases by enabling high-resolution analysis of cellular heterogeneity and molecular dynamics. Traditional technologies (e.g., bulk sequencing, routine histology) often lack cellular resolution, fail to capture heterogeneity among individual cells, and struggle to reveal subtle molecular changes in early pathogenesis, limiting their ability to clarify complex CNS disease mechanisms and develop precise diagnostic tools. This review comprehensively summarizes the latest advances in single-cell multi-omics methodologies, including genomics, transcriptomics, proteomics, metabolomics, and spatial omics, and their applications in elucidating the pathogenesis, diagnosis, and treatment of common CNS disorders. Representative diseases such as ischemic stroke, Alzheimer's disease, Parkinson's disease, viral meningitis, bacterial meningitis, multiple sclerosis, autism spectrum disorder, and depression are used as examples to discuss the current status and future prospects of single-cell multi-omics technologies in CNS disease research. Currently, these technologies have enabled the identification of rare pathogenic cell subsets, the mapping of cell-specific molecular pathways, and the discovery of potential diagnostic biomarkers in several common CNS disorders, though their clinical translation is still hindered by technical costs and standardization issues. In the future, the integration of single-cell multi-omics with spatial transcriptomics, artificial intelligence, and clinical data is expected to further decode the complex pathogenesis of CNS disorders, accelerate the development of targeted therapies, and promote the shift toward personalized medicine in CNS disease management-aligning with translational goals of neuropsychopharmacology.
Cognitive decline and dementia represent major and growing global health challenges, driven largely by population aging and increased longevity. Currently, more than 55 million people worldwide live with dementia, a figure projected to rise to approximately 153 million by 2050. Alzheimer's disease accounts for the majority of cases, and despite extensive research, effective disease-modifying therapies remain limited. Consequently, increasing attention has shifted toward prevention strategies targeting modifiable risk factors. Accumulating evidence indicates that dementia is not an inevitable consequence of aging and that up to 45 % of cases may be attributable to potentially modifiable lifestyle and environmental factors operating across the life course. Lifestyle behaviors-including diet, physical activity, smoking, alcohol consumption, sleep, and social and cognitive engagement-have emerged as key targets for intervention. In particular, adherence to healthy dietary patterns such as the Mediterranean, DASH, and MIND diets has been associated with better cognitive outcomes, while unhealthy dietary patterns may increase risk. However, findings across studies remain heterogeneous, and uncertainties persist regarding causality, optimal exposure timing, and specific lifestyle components. Recent large prospective cohorts, meta-analyses, umbrella reviews, and multidomain intervention trials have advanced understanding of these associations but have also highlighted important gaps, including limited randomized evidence and underrepresentation of diverse populations. This narrative review critically synthesizes current evidence on lifestyle factors and dietary patterns associated with cognitive decline and dementia risk, focusing on recent high-quality studies. By integrating findings across domains, it aims to clarify areas of consensus and uncertainty, inform prevention strategies, and identify priorities for future research and public health action. See also the graphical abstract(Fig. 1).
Alzheimer's disease (AD) is a global health challenge requiring early and accurate diagnosis, yet current clinical methods struggle with early stages. Deep learning approaches for MRI-based diagnosis face persistent challenges related to image quality issues, limited model generalization, and subtle inter-class variations. To address these limitations, this paper proposes a robust, end-to-end brain MRI-based framework for multi-class classification of AD stages. Positioned within the broader research priority of artificial intelligence and intelligent healthcare technologies, the proposed methodology incorporates an attention-based ensemble of deep learning models alongside an enhanced image preprocessing that uses Real-ESRGAN to mitigate common compression and resolution degradations in 2-D MRI slices. The ensemble makes use of the superior capabilities of the Swin Transformer to capture global contextual dependencies and EfficientNet-B3/MobileNetV2 for effective multi-scale feature extraction, with feature fusion performed using a Squeeze-and-Excitation attention mechanism. The experiments were performed on a publicly available Alzheimer's MRI dataset, resulting in classification accuracy of 94.47% and 92.28% for the two proposed frameworks. The robustness and clinical interpretability of the framework are emphasized through comprehensive metrics and qualitative analysis. This framework demonstrates promising benchmark performance on a standardized public dataset, highlighting the potential of cross-paradigm ensembles combined with super-resolution preprocessing.
The objective of the current research is to investigate the cognitive performance of male Alzheimer's disease rats in the context of the combined effects of exercise and metformin. The rats were divided into eight different groups. The Morris water maze (MWM) and the open field test (OFT) were employed to assess the cognitive functionality and motor activity of rats, respectively. The hippocampus of rats was subjected to histological evaluation, and expression of brain-derived neurotrophic factor (BDNF) was measured using the real-time polymerase chain reaction (RT-PCR) method. On concluding day of training, the d-gal-met100-exe group (D-galactose plus optimized 100mg/kg of metformin along with exercise) exhibited a diminished duration in the target quadrant (P < 0.0001) and covered a shorter distance to find the platform (P = 0.0004). On the day of the test, the distance covered in the target quadrant decreased in the d-gal group that received 120mg/kg of D-galactose (P = 0.0186) and significantly increased in the d-gal-met100-exe group compared to the d-gal group (P = 0.0002). The OFT indicated no substantial variations in distance or overall speed across the groups, suggesting that metformin did not affect motor activity. Based on the histology findings, in the d-gal-met100-exe group, fewer pyramidal cells led to less neuronal damage (P < 0.0001). In contrast, the BDNF gene in the hippocampus of the aforementioned group rose considerably as compared to the d-gal group (P = 0.0002). In general, the combined administration of metformin and exercise had a greater effect on enhancing memory and learning in Alzheimer's rats.
Magnetic resonance imaging (MRI) is central to the study and diagnosis of neurodegenerative diseases. Yet, no MRI biomarker is currently specific to a given neurodegenerative disease. This may result from the limited resolution of conventional MRI, which restricts detailed investigation of medial temporal lobe (MTL) subregions, a crucial hub for many neuropathologies. Moreover, in vivo MRI cannot be directly compared with neuropathological data, the gold standard for disease definition. Even when antemortem MRI and postmortem analyses are combined, the time gap between imaging and neuropathological examination allows pathogenic processes to progress, reducing the accuracy of these correlations. Over the past two decades, postmortem MRI has gained increasing interest because it enables long, motion-free acquisitions and the use of specialized coils and preclinical scanners, providing ultra-high spatial resolution. Additionally, it allows direct correspondence between imaging and neuropathological measures. Consequently, volumetric postmortem MRI, particularly investigations of the MTL, has become an increasingly common approach in Alzheimer's disease and related disorders (ADRD). This narrative review specifically focuses on volumetric postmortem MRI of the MTL and summarizes the main methodologies for anatomical postmortem MTL imaging in ADRD and recent advances in the characterization of neurodegenerative changes, from brain preparation to MRI acquisition. It also highlights the translational potential of volumetric postmortem MRI for developing in vivo biomarkers, optimizing imaging protocols and segmentation methods, and assessing the impact of proteinopathies. Finally, it outlines current limitations, technical challenges, and perspectives for future research.
Alzheimer's disease (AD) diagnostic guidelines emphasize subjective cognitive decline (SCD) preceding mild cognitive impairment (MCI), implicitly assuming awareness of cognitive decline (ACD) is preserved in preclinical AD. This study aimed to characterize a discrete clinical profile consistent with subtle amnestic anosognosia: decreased ACD, evaluating its association with multimodal core AD biomarkers in cognitively unimpaired (CU) individuals. We analyzed data from CU individuals with baseline CSF biomarkers and 3-year longitudinal neuropsychological assessment (ALFA+ cohort). Decreased ACD was defined by concurrent decline in episodic memory and cognitive awareness using robust longitudinal references (Free and Cued Selective Reminding Test, Memory Binding Test, Wechsler Memory Scale, and Subjective Cognitive Decline Questionnaire). Biomarker outcomes included plasma p-tau181, p-tau181/Aβ42, p-tau217; CSF p-tau181, Aβ42/40, p-tau181/Aβ42, p-tau217; Aβ ([¹⁸F]flutemetamol) and tau PET ([¹⁸F]RO948). Associations of ACD with AD biomarkers were evaluated using linear regression models. Sensitivity analysis was restricted to individuals with memory decline. 350 CU individuals were included (mean age 61 years; 60% female; mean education 14 years; 35% CSF Aβ-positive). Memory decline was identified in 61 (17%) individuals, of whom 25 (41%) exhibited concurrent awareness decline; meeting criteria for decreased ACD. This group demonstrated higher levels of AD pathology compared to the remaining sample. Among fluid biomarkers, CSF p-tau217 showed the strongest association. Neuroimaging revealed elevated frontoparietal Aβ PET, alongside temporal, insular, and frontal tau PET deposition. Sensitivity analysis confirmed that, although less pronounced, this pattern persists at the same threshold of memory decline. This study suggests that assessment of ACD may provide a crucial extension of current AD clinical frameworks.
Background/Objectives: Alzheimer's disease (AD) remains a significant global health challenge, characterised by a persistent resistance to traditional pharmacological interventions. While non-invasive brain stimulation (NIBS) techniques like transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS) show therapeutic promise, their limited depth of penetration restricts their efficacy in targeting deep-brain AD pathology. Transcranial focused ultrasound stimulation (tFUS) has emerged as a novel, non-invasive neuromodulatory tool capable of precise deep-brain targeting. This scoping review aims to systematically map the current evidence base regarding the neuromodulatory application of tFUS in AD. Methods: Following PRISMA-ScR guidelines, a scoping search was conducted across four major databases (Ovid MEDLINE, Embase, Web of Science, and CENTRAL). Studies were included if they investigated focused ultrasound stimulation (FUS) as a neuromodulatory intervention for AD, excluding applications involving blood-brain-barrier disruption via microbubbles. Two independent reviewers performed screening and data extraction, with inter-rater reliability assessed via Cohen's kappa. Results: Our analysis indicates that tFUS represents a safe and potent multi-modal intervention for AD that addresses both pathological protein aggregation and electrophysiological network failure. Its ability to modulate neuroplasticity and metabolic recovery suggests a promising therapeutic trajectory. Conclusions: Future research should prioritise the standardisation of acoustic protocols and the pursuit of longitudinal clinical cohorts to establish the long-term efficacy of this non-invasive technology.
Lecanemab is a monoclonal antibody targeting amyloid-β (Aβ) and is currently used in clinical practice for the treatment of early Alzheimer's disease (AD). However, noninvasive biomarkers reflecting its early efficacy are still unclear. This exploratory case report aims to investigate the combination of eye movement and gait analysis to quantitatively monitor shortterm functional changes during lecanemab treatment. Two male patients, both diagnosed with mild Alzheimer's disease through amyloid- PET and both with the APOE ε3/ε3 genotype, received intravenous lecanemab (10 mg/kg, every two weeks) for three months. Cognitive assessments (Montreal Cognitive Assessment, Mini- Mental State Examination, Clinical Dementia Rating), eye movement tests (smooth pursuit, overlapping saccades, anti-saccades), and gait analysis under single-task and dual-task conditions were conducted at baseline and follow-up. Patient 1 (79 years old) showed stable cognitive function, significant improvement in multiple eye movement parameters, and partial improvement in gait under single-task conditions. Patient 2 (60 years old) did not follow up on cognitive function tests as scheduled and showed inconsistent changes in eye movement parameters, but improved selected gait measures under dual-task conditions, particularly a shorter turning time. Neither patient experienced Amyloid-Related Imaging Abnormalities or infusion-related adverse events during the infusion process. This exploratory case report suggests that eye movement and gait analysis may be sensitive to short-term functional changes following lecanemab treatment, which were not consistently captured by traditional cognitive scales. These findings are hypothesis-generating and warrant further investigation in larger studies. Multimodal functional assessment may hold promise as a tool for monitoring early treatment effects in Alzheimer's disease.
Alzheimer's disease (AD) is a progressive neurodegenerative disorder driven by amyloid-β accumulation, tau hyperphosphorylation, oxidative stress, neuroinflammation, mitochondrial dysfunction, and cholinergic deficits. Despite extensive research, current FDA-approved therapies provide only modest symptomatic relief, underscoring the urgent need for safe and multi-targeted alternatives. This comprehensive review synthesizes evidence from in vitro, in vivo, and clinical studies on 15 medicinal plants and their 21 active compounds with therapeutic relevance to AD. Studies were included based on defined screening criteria: reported neuroprotective activity in at least one AD-related pathway, mechanistic evidence from preclinical or clinical investigations, and publication between 2015 and 2025. Analysis demonstrates that numerous plant extracts and isolated compounds including those from Allium sativum, Bacopa monnieri, Centella asiatica, Crocus sativus, Curcuma longa, Ginkgo biloba, Hericium erinaceus, Melissa officinalis, Nigella sativa, Salvia miltiorrhiza, Vitis vinifera, and others exert neuroprotective actions through convergent mechanisms. These include attenuation of oxidative and inflammatory pathways, inhibition of acetylcholinesterase and BACE-1, suppression of amyloid and tau pathology, enhancement of synaptic plasticity, mitochondrial support, and activation of neurotrophic signaling such as BDNF, TrkB and NRF2. Several compounds, including crocin, crocetin, curcumin, bilobalide, tanshinone IIA, bacosides, thymoquinone, and salvianolic acid B, demonstrate strong mechanistic activity across multiple AD-related pathways. Clinical trials further validate translational potential, with improvements reported in cognitive performance, behavioral symptoms, biomarker regulation, and daily functioning in individuals with mild cognitive impairment, AD, or age-related cognitive decline. Together, the evidence highlights medicinal plants as promising complementary or alternative strategies for modifying disease-relevant mechanisms and supporting cognitive health. Continued high-quality clinical investigations and optimized formulations are essential to advance these candidates toward therapeutic application.
Alzheimer's disease (AD) is a progressive neurodegenerative disorder marked by synaptic dysfunction, glial cell activation, and deterioration of neurons. Multiple pathways contribute to its pathophysiology, including β-amyloid (Aβ) plaque formation, intracellular neurofibrillary tangles, oxidative neuronal damage, and inflammatory responses. While Aβ deposition is considered an early trigger in the disease cascade, clinical symptom progression correlates more strongly with tau pathology and inflammatory responses. Recent concerns over data integrity in several high-profile AD studies have prompted critical re-evaluations of widely accepted hypotheses, emphasizing the urgent need for scientific transparency, reproducibility, and independent validation. In compiling this review, we prioritized findings supported by converging evidence from multiple experimental approaches and replication across independent cohorts. The hypothesis that an imbalance between Aβ42 synthesis and clearance is a central factor in AD has gained support from recent evidence, despite ongoing debate over the amyloid β-protein hypothesis. Dominant mutations associated with early-onset AD are primarily found in the amyloid precursor protein, which serves as the substrate for Aβ production, or in presenilin, the protease responsible for Aβ formation. The identification of presenilin as the catalytic site for β-secretase has provided crucial insights into AD pathogenesis. This review synthesizes current understanding of AD mechanisms, highlights emerging insights from multi-omics and spatial transcriptomic technologies, and discusses the evolving therapeutic landscape. Despite setbacks, the field continues to advance through methodological innovation and a revived interest in AD research integrity, offering hope for early diagnosis, more targeted treatments, and ultimately, disease-modifying therapies.