@article {pmid40913683,
year = {2025},
author = {Smoller, C and Schiller, E and Yamashita, K and Silverglate, BD and Grossberg, GT},
title = {Current and Emerging Pharmacological Approaches to Agitation in Alzheimer's Disease: A Narrative Review of New and Repurposed Therapies.},
journal = {Drugs},
volume = {},
number = {},
pages = {},
pmid = {40913683},
issn = {1179-1950},
abstract = {This narrative review explores current pharmacological treatments for agitation in Alzheimer's disease (AD). Agitation, a common and difficult-to-manage symptom in AD, often requires targeted intervention. While nonpharmacological methods, such as behavioral therapy and environmental modifications, are considered first line, they may not always be effective. In cases where these approaches fail, pharmacological treatment can become a necessary component of care. Historically, antipsychotics have been the mainstay of pharmacological treatment for agitation in AD; however, safety and efficacy concerns have prompted exploration into alternative treatments. The purpose of this narrative review is to synthesize current literature on pharmacological treatments for agitation in AD with a focus on new and repurposed drugs. It also examines agents that have failed to demonstrate clinical benefit, offering insights into the ongoing challenges of drug development in this area. This review synthesizes recent findings on various drug classes, including anticonvulsants, antipsychotics, selective serotonin reuptake inhibitors (SSRIs), atypical antidepressants, sedatives, anti-dementia drugs, dextromethorphan, and cannabinoids. Both brexpiprazole and risperidone have demonstrated efficacy and received approval from government agencies, including brexpiprazole in the USA and risperidone in parts of Europe. Despite these advances, concerns remain regarding their long-term use and safety profiles. As a result, multiple other therapies are currently being studied as possible alternative solutions. However, no other pharmacological agents are currently approved, underscoring the need for further research on safe and effective options for this vulnerable population.},
}

@article {pmid40913351,
year = {2025},
author = {Peng, D and Wei, P and Li, Z and Wei, R and Li, H and Li, S},
title = {The Role of P62/Nrf2/Keap1 Signaling Pathway in Lead-Induced Neurological Dysfunction.},
journal = {CNS neuroscience & therapeutics},
volume = {31},
number = {9},
pages = {e70566},
doi = {10.1111/cns.70566},
pmid = {40913351},
issn = {1755-5949},
support = {82160626//National Natural Science Foundation of China/ ; 81803281//National Natural Science Foundation of China/ ; },
mesh = {*Kelch-Like ECH-Associated Protein 1/metabolism ; *NF-E2-Related Factor 2/metabolism ; Animals ; *Signal Transduction/drug effects/physiology ; *Lead/toxicity ; *Sequestosome-1 Protein/metabolism ; Male ; Oxidative Stress/drug effects/physiology ; Mice ; Reactive Oxygen Species/metabolism ; Neurons/drug effects/metabolism ; Cells, Cultured ; Rats ; Autophagy/drug effects ; Mice, Inbred C57BL ; },
abstract = {BACKGROUND: Lead (Pb) exposure is recognized for its contribution to the development of neurodegenerative diseases. However, the precise mechanisms underlying Pb-induced neurological dysfunction remain elusive. This study aimed to investigate the role of oxidative stress and the autophagy-related P62/kelch like ECH-associated protein 1 (Keap1)/Nuclear factor erythroid 2-related factor 2 (Nrf2) pathway in neuronal impairment caused by Pb.

METHODS: By employing both in vivo and in vitro approaches, we explored the involvement of the P62/Nrf2/Keap1 pathway in Pb-induced neurotoxicity.

RESULTS: Our findings demonstrated that Pb exposure triggers excessive production of reactive oxygen species (ROS), upregulates Keap1 protein expressions, promotes Nrf2 degradation, and inhibits expression of antioxidant proteins such as heme Oxygenase-1 (HO-1) and glutathione peroxidase (GPx), resulting in oxidative damage in neurons. Furthermore, we observed that the autophagy protein P62 disrupts the normal autophagy process by interacting with the Nrf2/Keap1 axis, leading to an accumulation of Tau, a protein associated with Alzheimer's disease (AD), ultimately resulting in neurodegeneration. However, treatment with the antioxidant N-acetylcysteine, Nrf2 activator Artemisitene, and autophagy activator Rapamycin attenuated these detrimental changes.

CONCLUSION: The P62/Nrf2/Keap1 pathway mediates Pb-induced neuronal dysfunction and highlights its potential as a therapeutic target for mitigating the neurodegenerative effects associated with Pb exposure.},
}

*Kelch-Like ECH-Associated Protein 1/metabolism
*NF-E2-Related Factor 2/metabolism
Animals
*Signal Transduction/drug effects/physiology
*Lead/toxicity
*Sequestosome-1 Protein/metabolism
Male
Oxidative Stress/drug effects/physiology
Mice
Reactive Oxygen Species/metabolism
Neurons/drug effects/metabolism
Cells, Cultured
Rats
Autophagy/drug effects
Mice, Inbred C57BL

@article {pmid40912996,
year = {2025},
author = {Greeley, D and Nash, M and Herskowitz, B and Kim, F and Rock, J and Prins, N and Kim, S and Xi, T and Busam, JA and Tete, B and Choung, JJ and Sha, SJ},
title = {A phase 2 randomized, placebo-controlled study on the efficacy and safety of AR1001, a phosphodiesterase-5 inhibitor, in patients with mild-to-moderate Alzheimer's disease.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {},
number = {},
pages = {100337},
doi = {10.1016/j.tjpad.2025.100337},
pmid = {40912996},
issn = {2426-0266},
abstract = {BACKGROUND: AR1001 is a phosphodiesterase-5 inhibitor that produces improved cognitive performance and reduces amyloid-β and phosphorylated tau burdens in preclinical models of Alzheimer's disease (AD).

OBJECTIVES: To evaluate the safety and efficacy of AR1001 in participants with mild-to-moderate Alzheimer's disease (AD).

DESIGN: Randomized, double-blind, placebo-controlled phase 2 trial conducted at 21 sites in the United States.

PARTICIPANTS: Adults aged 55-80 years with mild-to-moderate dementia as determined by National Institutes of Aging-Alzheimer's Association (NIA-AA) stage 4 or 5 and Mini-mental State Exam (MMSE) score 16-26.

INTERVENTION: Once daily oral administration of placebo, 10 mg AR1001, or 30 mg AR1001 for 26 weeks followed by 26 weeks optional extension.

MEASUREMENTS: Co-primary efficacy endpoints were changes from baseline at Week 26 in Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-Cog 13) and Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change (ADCS-CGIC). Secondary endpoints included measures of cognition, daily living, and depression. Levels of plasma biomarkers pTau-181, pTau-217, Aβ42/40 ratio, glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL) were also examined.

RESULTS: A total of 210 participants were enrolled and 82% completed 26 weeks of treatment. AR1001 10 mg and 30 mg were well-tolerated with a similar safety profile compared to placebo. After 26 weeks, there were no differences in ADAS-Cog13, ADCS-CGIC, or in secondary efficacy endpoints between groups. Levels of plasma biomarkers pTau-181, pTau-217, and GFAP were improved in the 30 mg AR1001 group compared to placebo.

CONCLUSION: AR1001 was safe and well tolerated. Although primary efficacy endpoints were not met after 26 weeks of treatment, participants receiving 30 mg AR1001 showed favorable changes in AD-related plasma biomarkers compared to placebo.

TRIAL REGISTRATION: clinicaltrials.gov; NCT03625622.},
}

@article {pmid40912535,
year = {2025},
author = {Cheng, F and Gao, H and Yan, B and Chen, F and Lei, P},
title = {From Disinfectant to Neurodegeneration: Integrating Machine Learning and Mendelian Randomization Reveals Triclosan as A Novel Environmental Risk Factor for Alzheimer's Disease.},
journal = {Environmental pollution (Barking, Essex : 1987)},
volume = {},
number = {},
pages = {127068},
doi = {10.1016/j.envpol.2025.127068},
pmid = {40912535},
issn = {1873-6424},
abstract = {This study systematically investigated the association between triclosan (TCS) exposure and Alzheimer's disease (AD) risk via integrated bioinformatics approaches. TCS-AD-related genes were identified using bioinformatics tools and public databases, followed by the screening of key genes through multi-model machine learning algorithms (LASSO, SVM-RFE, RF) to mitigate random errors in small sample sizes. DRD2 was confirmed as the most robust core gene by LASSO confidence interval analysis and SHAP evaluation, while APP and SLC6A3 were validated through cross-method intersection. Findings from functional enrichment analysis, Mendelian randomization, and molecular docking demonstrated that TCS may affect AD pathogenesis through these key genes. Moreover, a stable AD risk scoring model and predictive formula were developed via logistic regression analysis of T-A-Key Genes. This study constitutes an innovative and transformative research endeavor. Building upon the understanding of TCS-induced neurotoxicity, it extends to the clinical translational direction of predicting AD onset risk, thereby establishing a quantitative association model of "environmental exposure-core genes-disease risk. " It not only provides novel evidence for the potential role of TCS neurotoxicity as an environmental pathogenic factor in AD, emphasizing the necessity of prioritizing risk management of daily chemical exposure in AD prevention and treatment, but also offers a scientific foundation for the formulation of public health policies aimed at preventing long-term TCS exposure.},
}

@article {pmid40912368,
year = {2025},
author = {Wang, J and Qiao, Z and Cao, X and Li, H and Wang, Y and Jiao, Q and Chen, X and Du, X},
title = {G Protein-coupled receptors: key targets for maintaining the function of basal ganglia-thalamus-cortical circuits in Parkinson's disease.},
journal = {Biochemical pharmacology},
volume = {},
number = {},
pages = {117303},
doi = {10.1016/j.bcp.2025.117303},
pmid = {40912368},
issn = {1873-2968},
abstract = {Parkinson's Disease (PD), the second most common neurodegenerative disease after Alzheimer's disease, is clinically characterized by resting tremor, rigidity and postural balance disorder. Its pathological essence is the progressive degenerative death of dopaminergic neurons in the substantia nigra pars compacta (SNpc), leading to a significant decrease in striatal dopamine (DA) levels. This results in the dysfunction of basal ganglia-thalamus-cortex (BGTC) circuit. This circuit is the core neural circuit of motor control, and its abnormality not only directly causes the motor symptoms of PD, but also participates in the cascade of disease progression through the disorder of neurotransmitter signals. At present, DA replacement therapy and DA receptors (DARs) agonists are still the main methods of clinical treatment, but single therapy cannot fully correct the imbalance of other neurotransmitter systems, which has significant limitations in long-term efficacy and symptom management. G protein-coupled receptors (GPCRs), as the largest family of membrane proteins, have become important targets for PD treatment due to their extensive participation in physiological regulatory networks and excellent drug development potential. These transmembrane signaling molecules play important roles in multiple key nodes in the pathological process of PD by precisely regulating the release of neurotransmitters, the maintenance of synaptic plasticity and the dynamic balance of neural circuits. Here, we review the transition of BCTG in the context of PD and then focus on the pathological cascade of GPCRs mediating PD in this loop. Finally, we update the clinical trials or approvals of GPCR drugs under investigation for the treatment of PD.},
}

@article {pmid40912064,
year = {2025},
author = {Ali, N and Al-Rejaie, SS and Babu, MA and Nayak, P and VenuPrasad, KD and Mohany, M and Singh, TG and Akhter, MS and Fareed, M and Tyagi, Y and Bansal, N and Puri, S},
title = {Exploring the bioactive constituents from spices targeting N-methyl-d-aspartate receptors: An in silico and in vitro approach to identify druggable leads against neurological disability.},
journal = {Bioorganic & medicinal chemistry},
volume = {130},
number = {},
pages = {118378},
doi = {10.1016/j.bmc.2025.118378},
pmid = {40912064},
issn = {1464-3391},
abstract = {N-methyl-d-aspartate (NMDA) receptors are validated druggable targets for the treatment of Alzheimer's and other associated neurological conditions, particularly in individuals with disabilities. Considering the excitotoxicity associated with NMDA receptors, which leads to neuronal damage, cognitive impairment, and limitations of current therapeutic regimens, better therapeutic candidates are required. One of the validated drug discovery approaches is computer-assisted drug discovery, supplemented by molecular docking, mechanics, and dynamics. To this end, we curated 134 bioactive constituents derived from spices. These were subjected to high-throughput virtual screening (HTVS) considering the pharmacophoric features of the NMDA receptor. Molecular docking, followed by molecular mechanics and dynamics, indicated that curcumin and quercetin could plausibly bind to the NMDA receptor in comparison to memantine. In vitro ELISA-based analysis revealed that curcumin may inhibit the NMDA receptor with an IC50 of 2.36 μM compared to memantine's 736.48 nM, employed as a positive control. However, targeting the neuronal receptor NMDA requires that the ligand efficiently cross the blood-brain barrier (BBB). To overcome this challenge, we performed a rational bioisosteric replacement strategy to potentially optimize the pharmacokinetic features of curcumin without affecting its NMDA binding. We generated 150 bioisosteres of curcumin, and through extensive computational analyses, the top 5 scoring molecules were further validated via a molecular dynamics approach. However advantageous, in the present work, curcumin or its proposed derivatives have not been corroborated by extensive biological investigation. It is a prototype study to identify the druggable leads from the spices that have the potency to interact and inhibit NMDA. Owing to this, the mechanism of action is not fully elucidated. Further, the work upon validation (biologically) may serve as a useful pharmacophore (tool molecule) using which NMDA may be downregulated. The designed derivatives thus open avenues to synthesize and biologically test them against NMDA inhibition, plausibly establishing their roles in Alzheimer's and related disabilities.},
}

@article {pmid40911712,
year = {2025},
author = {Wang, G and Li, Y and McDade, E and Xiong, C and Hartz, SM and Bateman, RJ and Morris, JC and Schneider, LS and , },
title = {Clinical progression on CDR-SB©: Progression-free time at each 0.5 unit level in dominantly inherited and sporadic Alzheimer's disease populations.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {9},
pages = {e70643},
doi = {10.1002/alz.70643},
pmid = {40911712},
issn = {1552-5279},
support = {U19AG032438//The Dominantly Inherited Alzheimer Network/ ; SG-20-690363-DIAN//National Institute on Aging (NIA), the Alzheimer's Association/ ; HI21C0066//Ministry of Health & Welfare and Ministry of Science and ICT, Republic of Korea/ ; U01 AG024904/NH/NIH HHS/United States ; W81XWH-12-2-0012//Department of Defense/ ; U01AG042791//National Institute on Aging of the National Institutes of Health/ ; U01AG042791-S1//National Institute on Aging of the National Institutes of Health/ ; R01AG046179//National Institute on Aging of the National Institutes of Health/ ; R01AG053267//National Institute on Aging of the National Institutes of Health/ ; R01AG053267-S1//National Institute on Aging of the National Institutes of Health/ ; R01AG068319//National Institute on Aging of the National Institutes of Health/ ; 1U01AG059798//National Institute on Aging of the National Institutes of Health/ ; P30AG066530//National Institute on Aging of the National Institutes of Health/ ; U01AG042791//National Institute on Aging of the National Institutes of Health/ ; U01AG042791-S1//National Institute on Aging of the National Institutes of Health/ ; R01AG046179//National Institute on Aging of the National Institutes of Health/ ; R01AG053267//National Institute on Aging of the National Institutes of Health/ ; R01AG053267-S1//National Institute on Aging of the National Institutes of Health/ ; R01AG068319//National Institute on Aging of the National Institutes of Health/ ; 1U01AG059798//National Institute on Aging of the National Institutes of Health/ ; P30AG066530//National Institute on Aging of the National Institutes of Health/ ; U01AG052564//National Institute on Aging of the National Institutes of Health/ ; },
mesh = {Humans ; *Alzheimer Disease/genetics/drug therapy/diagnosis ; *Disease Progression ; Female ; Male ; Aged ; *Mental Status and Dementia Tests ; Cohort Studies ; Middle Aged ; Neuropsychological Tests ; },
abstract = {INTRODUCTION: Clinical Dementia Rating Sum of Boxes (CDR-SB) is a reliable and clinically meaningful composite for assessing treatment effects in Alzheimer's disease (AD) clinical trials. Small CDR-SB differences at the end of a trial often lead to controversy in deriving clinically meaningful interpretations.

METHODS: We estimated progression-free time (PFT) participants remained at each 0.5 unit CDR-SB increment in dominantly inherited AD (DIAD) and sporadic AD populations, evaluating its potential as an alternative measure of treatment effects.

RESULTS: PFT is longer at CDR-SB ≤ 2.0 (1-2 years) and shorter at CDR-SB ≥ 5 (≤ 0.33) in the Alzheimer's Disease Neuroimaging Initiative cohort. The DIAD cohort showed similar but shorter times. Using PFT, continuous lecanemab treatment for 3 years is estimated to delay disease progression by 0.62 years in the sporadic population.

DISCUSSION: PFT provides a benchmark for expressing clinical progression and treatment effects and can be applied particularly during open-label extensions and single-arm trials without placebo comparisons.

HIGHLIGHTS: We estimated the progression-free time at each 0.5 unit Clinical Dementia Rating Sum of Boxes increment in dominantly inherited Alzheimer's disease (AD) and sporadic AD populations. We proposed using progression-free time to estimate treatment effects in open-label extension or single-arm studies. If further validated, progression-free time could serve as a benchmark for assessing clinical progression and treatment effects.},
}

Humans
*Alzheimer Disease/genetics/drug therapy/diagnosis
*Disease Progression
Female
Male
Aged
*Mental Status and Dementia Tests
Cohort Studies
Middle Aged
Neuropsychological Tests

@article {pmid40911700,
year = {2025},
author = {Maria, and Khan, A and Ajaj, R and Rauf, A and , and Shah, ZA and Ahmad, Z and Hemeg, HA and Rashid, U},
title = {Secondary metabolites isolated from Fernandoa adenophylla (Wall. ex G.Don) steenis as multitarget inhibitors of cholinesterases for the treatment of Alzheimer's Disease, followed by molecular docking studies.},
journal = {PloS one},
volume = {20},
number = {9},
pages = {e0331119},
doi = {10.1371/journal.pone.0331119},
pmid = {40911700},
issn = {1932-6203},
mesh = {*Cholinesterase Inhibitors/pharmacology/chemistry/therapeutic use/isolation & purification ; Molecular Docking Simulation ; *Alzheimer Disease/drug therapy/enzymology ; Butyrylcholinesterase/metabolism/chemistry ; Acetylcholinesterase/metabolism/chemistry ; Humans ; *Plant Extracts/chemistry/pharmacology ; Secondary Metabolism ; },
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder categorized by the progressive loss of cognitive function, with acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) as key therapeutic targets. In this study, we report the isolation, characterization, and evaluation of the cholinesterase inhibitory potential of phytochemicals from Fernandoa adenophylla (Wall. ex G. Don) Steenis, a plant known for its medicinal properties. Using in-vitro enzyme inhibition assays, we identified five bioactive compounds, including lapachol (1), α-lapachone (2), peshawaraquinone (3), dehydro-α-lapachone (4), and an indanone derivative (5), which demonstrated significant inhibition of AChE and BuChE. The compounds exhibited varied inhibitory potency, with peshawaraquinone (3) showing the most promising AChE (IC50 = 0.90 ± 0.04 µM) and BuChE (IC50 = 8.39 ± 0.14 µM) inhibition, followed by dehydro-α-lapachone (4), which exhibited an AChE IC50 value of 2.64 ± 0.08 µM. Further, the selectivity index (SI) for AChE over BuChE was highest for dehydro-α-lapachone (SI = 21.1), suggesting its potential as a selective inhibitor. Molecular docking studies provided insights into the binding interactions between these compounds and the enzyme active sites, highlighting key interactions that may contribute to their inhibitory activity. These findings suggest that phytochemicals from F. adenophylla possess significant cholinesterase inhibition potential and may serve as leads for the development of novel therapeutic agents for Alzheimer's disease.},
}

*Cholinesterase Inhibitors/pharmacology/chemistry/therapeutic use/isolation & purification
Molecular Docking Simulation
*Alzheimer Disease/drug therapy/enzymology
Butyrylcholinesterase/metabolism/chemistry
Acetylcholinesterase/metabolism/chemistry
Humans
*Plant Extracts/chemistry/pharmacology
Secondary Metabolism

@article {pmid40911470,
year = {2025},
author = {Yamamoto, N and Yuzu, K and Morishima, K and Inoue, R and Sugiyama, M and Koyama, D and Chatani, E},
title = {Targeting Both Monomer and Oligomer with Fibrinogen Efficiently Suppresses Amyloid Fibril Formation and Cell Toxicity of Amyloid β 1-42.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.5c00562},
pmid = {40911470},
issn = {1948-7193},
abstract = {The development of drugs for Alzheimer's disease, which accounts for over half of all dementia cases, remains challenging. Amyloid β 1-42 (Aβ42) is widely recognized for its deposition in the brains of patients with Alzheimer's disease. Furthermore, Aβ42-induced cell toxicity likely plays a role in disease onset. Molecular species present in the early stages, such as monomers and oligomers, are appropriate therapeutic targets for suppressing amyloid fibril formation and cell toxicity. In this study, we investigated the effects of bovine fibrinogen (bFg) and human fibrinogen (hFg) since these molecules have been known to exhibit chaperone-like activities. Our findings indicate that bFg exerts a strong inhibitory effect on amyloid fibril formation. Dot blot assays, analytical ultracentrifugation (AUC), and atomic force microscopy (AFM) suggest that bFg interacts with both Aβ42 monomers and oligomers. In contrast, human fibrinogen (hFg), which interacts only with oligomers, exhibits a weaker inhibitory effect on amyloid fibril formation. Moreover, bFg significantly rescued cells from Aβ42-induced toxicity, whereas hFg provided only partial protection. These findings underscore the potential of molecules targeting early stage Aβ42 species as promising candidates for Alzheimer's disease treatment.},
}

@article {pmid40911101,
year = {2025},
author = {Qian, J and Ren, S and Ren, T and Shi, R and Qiao, L and Kang, J},
title = {Astrocyte Autophagy in Neurodegenerative Diseases: Current Progress in Mechanisms and Therapeutics.},
journal = {Neurochemical research},
volume = {50},
number = {5},
pages = {287},
pmid = {40911101},
issn = {1573-6903},
support = {202310472004//the College Students' Innovation and Entrepreneurship Training Program/ ; 82071326//the National Natural Science Foundation of China/ ; 232102310288//Key Technologies R&D Program of Henan Province/ ; 252300421395//Natural Science Foundation of Henan/ ; 505511, XYBSKYZZ202124, 506017//Doctoral Scientific Research Foundation of Xinxiang Medical University/ ; },
mesh = {Humans ; *Autophagy/physiology/drug effects ; *Neurodegenerative Diseases/metabolism/pathology/drug therapy/therapy ; *Astrocytes/metabolism/pathology/drug effects ; Animals ; Oxidative Stress/physiology ; },
abstract = {Astrocytes, the most abundant and functionally diverse glial cell type in the brain, play a crucial role in maintaining cellular homeostasis and promoting neuronal survival. Autophagy is the process of transferring senescent, denatured, or damaged proteins and organelles from cells to lysosomes for degradation. However, recent research on autophagy in the central nervous system has focused on neurons. In this paper, we reviewed the latest findings on astrocyte autophagy and its mechanisms in regulating neurodegenerative disorders. It influences the pathological processes of Alzheimer's disease, Parkinson's disease, Huntington's disease, and other synucleinopathies (including dementia with Lewy bodies and Parkinson's disease dementia) by regulating oxidative stress and inflammatory responses, as well as aberrant protein aggregation and folding. Furthermore, we listed medications that can prevent or treat neurodegenerative disorders by modulating astrocyte autophagy pathways, providing new insights into preventive and therapeutic strategies for neurodegenerative diseases.},
}

Humans
*Autophagy/physiology/drug effects
*Neurodegenerative Diseases/metabolism/pathology/drug therapy/therapy
*Astrocytes/metabolism/pathology/drug effects
Animals
Oxidative Stress/physiology

@article {pmid40910917,
year = {2025},
author = {Xin, YX and Xiao, YL},
title = {[Research progress on the relationship between traumatic brain injury and neurogenic lower urinary tract dysfunction].},
journal = {Zhonghua nan ke xue = National journal of andrology},
volume = {31},
number = {7},
pages = {650-653},
pmid = {40910917},
issn = {1009-3591},
mesh = {Humans ; *Brain Injuries, Traumatic/complications ; *Urinary Bladder, Neurogenic/etiology ; Risk Factors ; },
abstract = {Urinary dysfunction caused by central nervous system or peripheral nerve disease represents a significant global medical and social problem. Neurologic abnormalities, including traumatic brain injury (TBI), stroke, Alzheimer's disease, and Parkinson's disease, have been identified as potential risk factors for neurogenic urinary tract dysfunction. The relationship between TBI and neurogenic lower urinary tract dysfunction (NLUTD) will be introduced in this article, with the mechanisms, clinical manifestations, diagnostic methods, and treatment strategies of NLUTD after TBI being evaluated as well, which provides a reference for the diagnosis and treatment.},
}

Humans
*Brain Injuries, Traumatic/complications
*Urinary Bladder, Neurogenic/etiology
Risk Factors

@article {pmid40910390,
year = {2025},
author = {Frederiksen, KS and Gramkow, MH and Hasselbalch, SG and Law, I and Waldemar, G},
title = {[Anti-amyloid antibodies for the treatment of early-stage Alzheimer's disease].},
journal = {Ugeskrift for laeger},
volume = {187},
number = {35},
pages = {},
doi = {10.61409/V03250217},
pmid = {40910390},
issn = {1603-6824},
mesh = {Humans ; *Alzheimer Disease/drug therapy/diagnosis/immunology ; *Amyloid beta-Peptides/immunology/antagonists & inhibitors ; Antibodies, Monoclonal, Humanized/therapeutic use/adverse effects ; *Antibodies, Monoclonal/therapeutic use/adverse effects ; },
abstract = {Alzheimer's disease is the most common neurodegenerative dementia disorder and is associated with several negative health outcomes. Current treatment consists of symptomatic treatment and supportive measures. However, advances have led to the development of antibodies towards beta-amyloid, which likely plays a pivotal role in the pathophysiology. Lecanemab and donanemab have shown efficacy in the early stages of Alzheimer's disease but are also associated with a risk of cerebral haemorrhages and oedema. The introduction of these antibodies will require adjustment of diagnostic and management pathways as discussed in this review.},
}

Humans
*Alzheimer Disease/drug therapy/diagnosis/immunology
*Amyloid beta-Peptides/immunology/antagonists & inhibitors
Antibodies, Monoclonal, Humanized/therapeutic use/adverse effects
*Antibodies, Monoclonal/therapeutic use/adverse effects

@article {pmid40910338,
year = {2025},
author = {Navarra, AN and Wang, LA and Al-Sahlani, H and Liu, AJ and Doraiswamy, PM},
title = {Severe Persistent Urinary Retention Following Treatment With Intravenous Lecanemab: Urinary Retention With IV Lecanemab.},
journal = {Pharmacotherapy},
volume = {},
number = {},
pages = {},
doi = {10.1002/phar.70060},
pmid = {40910338},
issn = {1875-9114},
abstract = {Lecanemab is an amyloid-targeted antibody indicated for treating patients with amyloid-confirmed early Alzheimer's Disease in mild dementia or mild cognitive impairment stages. We report here a case of a subject with early stage of Alzheimer's Disease dementia, amyloid positive, who developed severe acute urinary retention following his first dose of intravenous lecanemab. His urinary retention resolved after a week but recurred following the second intravenous dose 2 weeks later. Lecanemab was discontinued, but the urinary retention has persisted for 8 months indicating possible permanent adverse impact on the bladder. The Naranjo causality probability score was 6. The incidence of urinary retention with intravenous lecanemab is not known but given that elderly patients with dementia may have multiple risks for bladder dysfunction, clinicians should remain vigilant. It is hoped that newer formulations, such as subcutaneous lecanemab, may prove safer in such patients.},
}

@article {pmid40910212,
year = {2025},
author = {Zhang, YY and Cheng, YY and Guan, W},
title = {Betaine, a Potential Therapeutic Alternative for the Treatment of Depression.},
journal = {Current drug targets},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113894501394957250818110931},
pmid = {40910212},
issn = {1873-5592},
abstract = {Depression is a debilitating psychiatric disorder characterized by loss of interest, anhedonia, and social isolation, which is projected to become the leading cause of disability worldwide by 2030. Despite the greater economic and social burden imposed by depression, the precise pathophysiology underlying the development of depression remains elusive. Betaine (N, N, N-trimethylglycine), an amino acid derivative, is widely distributed in various animals and plants and has been shown to have numerous beneficial effects, including antioxidant activities, anti-inflammatory functions, regulation of energy metabolism, and reduction of endoplasmic reticulum stress. It has been used to treat Alcohol-Associated Liver Disease (AALD), type 2 diabetes, cancer, obesity, and Alzheimer's Disease (AD). Interestingly, accumulating evidence has shown that betaine exerts a significant role in alleviating depressive-like behavior in patients and animals resulting from chronic stress. Although the antidepressant effects of betaine have not been compared with traditional antidepressants with insufficient verification, based on the neurobiological mechanisms of depression, it may be a potential alternative medicine for the treatment of depression. This is the first review aiming to provide a comprehensive overview of the remarkable effects of betaine in the pathophysiology of depression. These pieces of evidence are of great importance for deepening our understanding of the antidepressant mechanism of betaine, so as to develop betaine supplements for the supplementary treatment of depression.},
}

@article {pmid40910023,
year = {2025},
author = {Shahid, SB and Kaikaus, M and Kabir, MH and Yousuf, MA and Azad, AKM and Al-Moisheer, AS and Alotaibi, N and Alyami, SA and Bhuiyan, T and Moni, MA},
title = {Novel deep learning for multi-class classification of Alzheimer's in disability using MRI datasets.},
journal = {Frontiers in bioinformatics},
volume = {5},
number = {},
pages = {1567219},
pmid = {40910023},
issn = {2673-7647},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is one of the most common neurodegenerative disabilities that often leads to memory loss, confusion, difficulty in language and trouble with motor coordination. Although several machine learning (ML) and deep learning (DL) algorithms have been utilized to identify Alzheimer's disease (AD) from MRI scans, precise classification of AD categories remains challenging as neighbouring categories share common features.

METHODS: This study proposes transfer learning-based methods for extracting features from MRI scans for multi-class classification of different AD categories. Four transfer learning-based feature extractors, namely, ResNet152V2, VGG16, InceptionV3, and MobileNet have been employed on two publicly available datasets (i.e., ADNI and OASIS) and a Merged dataset combining ADNI and OASIS, each having four categories: Moderate Demented (MoD), Mild Demented (MD), Very Mild Demented (VMD), and Non Demented (ND).

RESULTS: Results suggest the Modified ResNet152V2 as the optimal feature extractor among the four transfer learning methods. Next, by utilizing the modified ResNet152V2 as a feature extractor, a Convolutional Neural Network based model, namely, the 'IncepRes', is proposed by fusing the Inception and ResNet architectures for multiclass classification of AD categories. The results indicate that our proposed model achieved a standard accuracy of 96.96%, 98.35% and 97.13% for ADNI, OASIS, and Merged datasets, respectively, outperforming other competing DL structures.

DISCUSSION: We hope that our proposed framework may automate the precise classifications of various AD categories, and thereby can offer the prompt management and treatment of cognitive and functional impairments associated with AD.},
}

@article {pmid40909873,
year = {2025},
author = {Wang, X and Dong, B and Gan, Q and Li, J and Wu, P and Guan, Y and Wang, J},
title = {Unraveling the Vicious Cycle: Oxidative Stress and Neurotoxicity in Neurodegenerative Diseases.},
journal = {FASEB bioAdvances},
volume = {7},
number = {8},
pages = {e70041},
pmid = {40909873},
issn = {2573-9832},
abstract = {Oxidative stress is characterized by an imbalance between the production and elimination of free radicals, where the rate of free radical generation surpasses the rate of their removal. This imbalance can lead to tissue and organ damage, contributing to the pathogenesis of various diseases. The nervous system, due to its high oxygen consumption, is particularly susceptible to oxidative stress. Numerous neurotoxins can induce neurotoxicity through oxidative stress, thereby contributing to the onset of neurodegenerative diseases, such as Parkinson's disease, Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis. Furthermore, neurotoxicity can exacerbate oxidative stress by disrupting mitochondrial metabolism and impairing the activity of antioxidant enzymes, thereby intensifying neurotoxic effects. This review examines the mechanisms underlying the interaction between oxidative stress and neurotoxicity and explores strategies to mitigate neurotoxicity by reducing oxidative stress, with the aim of informing future clinical approaches for the treatment of neurodegenerative diseases.},
}

@article {pmid40908886,
year = {2025},
author = {Singh, T and Yadav, R and Hazra, S},
title = {Atomically Dispersed Ru Catalyst Locked in Knitting Aryl Network Polymers: A Robust Heterogeneous Catalyst for Borrowing Hydrogenation in Aqueous Micelles.},
journal = {ACS applied materials & interfaces},
volume = {},
number = {},
pages = {},
doi = {10.1021/acsami.5c09711},
pmid = {40908886},
issn = {1944-8252},
abstract = {Fabrication of water-stable and atomically dispersed ruthenium catalysts for sustainable borrowing hydrogenation (BH) reactions is a long-standing challenge. Herein, we developed an atomically dispersed Ru catalyst that has been successfully employed for BH reactions in aqueous micelles under mild conditions. The micellar cooperativity with the hydrophobic knitted aryl polymers (KAPs) led to the formation of microconfinements, which act as the confined space for catalysis in water. The catalyst was characterized by using various techniques such as transmission electron microscopy (TEM), scanning electron microscopy (SEM), high-resolution transmission electron microscopy (HR-TEM), aberration-corrected high-angle annular dark-field scanning transmission electron microscopy (AC-HAADF-STEM), X-ray photoelectron spectroscopy (XPS), and X-ray absorption spectroscopy (XAS). Confocal laser scanning microscopy (CLSM) and fluorescence lifetime imaging microscopy (FLIM) have been used to understand the role of micelles, reagents, and materials in the generation of confined space in water. The catalyst was found to be recyclable for five cycles without a significant loss of its catalytic activity. We have also demonstrated a 1 g scale reaction for the alkylation of acetophenone and synthesis of Donepezil, a marketed drug for the treatment of Alzheimer's disease, using our method.},
}

@article {pmid40908772,
year = {2025},
author = {Faysal, M and Zehravi, M and Sutradhar, B and Al Amin, M and Shanmugarajan, TS and Arjun, UVNV and Ethiraj, S and Durairaj, A and Dayalan, G and Ahamad, SK and Rab, SO and Raman, K and Emran, TB},
title = {The Microbiota-Gut-Brain Connection: A New Horizon in Neurological and Neuropsychiatric Disorders.},
journal = {CNS neuroscience & therapeutics},
volume = {31},
number = {9},
pages = {e70593},
doi = {10.1111/cns.70593},
pmid = {40908772},
issn = {1755-5949},
mesh = {Humans ; *Gastrointestinal Microbiome/physiology ; *Mental Disorders/microbiology/metabolism/therapy ; *Nervous System Diseases/microbiology/metabolism/therapy ; *Brain/metabolism ; Animals ; Dysbiosis ; *Brain-Gut Axis/physiology ; Probiotics ; },
abstract = {INTRODUCTION: The microbiota-gut-brain axis (MGBA), a complex two-way connection between the gut microbiota and the brain, has become a key regulator of neurological and neuropsychiatric disorders. Neurological disorders and gut microbiota dysbiosis are linked to these diseases. Changes in gut microbiota can lead to neurotransmitter imbalances, oxidative stress, and neuroinflammation. Gut dysbiosis may contribute to the development of diseases such as depression, autism, schizophrenia, bipolar disorder, Parkinson's disease, Alzheimer's disease, dementia, multiple sclerosis, epilepsy, anxiety, and autism spectrum disorders through immunological regulation, neuroinflammation, and neurotransmitter metabolism changes.

METHOD: This review systematically sourced articles related to microbiota gut brain axis, neurological disorders, neuropsychiatric disorders and clinical studies from major medical databases, including Scopus, PubMed, and Web of Science.

RESULTS: This review explores the molecular processes underlying MGBA interactions, including vagus nerve signaling, systemic immunological responses, and metabolites produced by microorganisms. The discussion explores the potential of microbiome-targeted treatments like fecal microbiota transplantation, probiotics, and prebiotics as effective treatment methods. The comprehension of the MGBA can revolutionize neurology and psychiatry, introducing innovative diagnostic and therapeutic approaches. Multiple elements, including diet, metabolism, age, stress, and medications, shape the human gut microbiota, and intestinal imbalances can lead to CNS diseases. The MGBA interacts with gut bacteria, and gut dysbiosis is associated with neurological disorders.

CONCLUSIONS: The review demonstrates the correlation between gut microbiota and neurologically associated diseases, highlighting its importance in neurogenesis, mental development, emotions, and behaviors. MGBA, mediated by microbial metabolites, affects brain function and neuroinflammation. Interventions like fetal microbiota transplantation, probiotics, and prebiotics can improve microbial balance, but more clinical research is needed.},
}

Humans
*Gastrointestinal Microbiome/physiology
*Mental Disorders/microbiology/metabolism/therapy
*Nervous System Diseases/microbiology/metabolism/therapy
*Brain/metabolism
Animals
Dysbiosis
*Brain-Gut Axis/physiology
Probiotics

@article {pmid40908698,
year = {2025},
author = {Singh, A and Maheshwari, S and Ansari, VA and Verma, A and Ansari, TM and Akhtar, J and Ahsan, F and Vishwakarma, VK and Wasim, R},
title = {Dendrimers: Advancing Therapeutic Strategies for Dementia.},
journal = {Current aging science},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118746098343913250818112618},
pmid = {40908698},
issn = {1874-6128},
abstract = {Dementia, characterized by a progressive decline in cognitive function, poses a significant challenge to global healthcare systems, with current therapeutic approaches offering limited efficacy. The development of nanotechnology-based drug delivery systems has introduced promising avenues for enhancing the treatment of neurodegenerative disorders such as Alzheimer's disease. Dendrimers, with their highly branched, nanoscale structure, provide an innovative platform for targeted drug delivery to the brain. Dendrimers serve as nanoscale drug carriers that facilitate controlled drug release, enhance bioavailability, and improve penetration across the blood-brain barrier (BBB), leading to superior therapeutic efficacy in neurodegenerative disorders. In particular, dendrimers can encapsulate both hydrophilic and hydrophobic drugs, increasing their stability and minimizing systemic side effects. This review explores the unique properties of dendrimers, focusing on their potential as drug delivery vehicles in dementia treatment. We also highlight advancements in the design and application of dendrimer-based therapeutics, emphasizing their role in targeting key pathological mechanisms underlying dementia. Through these approaches, dendrimers represent a promising strategy for developing more effective and personalized treatment modalities for patients suffering from cognitive impairment and dementia.},
}

@article {pmid40908696,
year = {2025},
author = {Paul, S and Tiwari, P and Dubey, S},
title = {Precision Enzyme: Targeted Drug Discovery in Neurodegenerative Disorders.},
journal = {Protein and peptide letters},
volume = {},
number = {},
pages = {},
doi = {10.2174/0109298665391103250825102319},
pmid = {40908696},
issn = {1875-5305},
abstract = {INTRODUCTION: Neurodegenerative disorders such as Alzheimer's, Parkinson's, and ALS are characterized by progressive neuronal dysfunction with limited therapeutic options. Recent advances in molecular biology and drug development have highlighted the therapeutic promise of precision enzyme targeting, offering novel strategies for disease modulation and symptom management.

METHODS: A comprehensive literature review spanning recent/current was conducted using PubMed, Scopus, and ScienceDirect. Studies focusing on enzyme-based targets, high-throughput screening, and molecular docking in neurodegeneration were included. Thematic synthesis was employed to categorize findings based on enzyme class, disease relevance, and therapeutic outcomes.

RESULTS: Key enzyme families such as kinases, proteases, and oxidoreductases were identified as pivotal modulators in disease progression. Emerging enzyme-targeted compounds demonstrated enhanced bioavailability, blood-brain barrier permeability, and disease-specific efficacy. Novel screening platforms and computational modeling enabled the precise selection of inhibitors, significantly improving the therapeutic index and reducing off-target effects.

DISCUSSION: Targeting enzymes implicated in neuroinflammation, oxidative stress, and protein misfolding has shown disease-modifying potential. Integrating precision drug discovery tools, such as AI-assisted modeling and enzyme kinetics, supports rational drug design. However, translational challenges persist due to variability in enzyme expression and disease heterogeneity.

CONCLUSION: Future research should focus on refining enzyme inhibitors and integrating biomarkers to facilitate personalized treatment strategies for neurodegenerative disorders. As the understanding of enzymatic roles in neurodegeneration deepens, precision enzyme-targeted drug discovery holds significant promise in transforming neurotherapeutic approaches.},
}

@article {pmid40908524,
year = {2025},
author = {Oba, GMJ and Sahu, R and Shah, K and Paliwal, D and Kumar Sah, A and Thakur, A},
title = {Current Developments in the Pharmacological Activities and Synthesis of Carbazole Derivatives.},
journal = {Mini reviews in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113895575407122250822095143},
pmid = {40908524},
issn = {1875-5607},
abstract = {The growing prevalence of multidrug resistance and its detrimental effects pose a significant threat to public health, which is one reason for the current interest in the introduction of novel agents. To combat this adverse effect and drug resistance, numerous drugs have been developed over time, and their safety is still being evaluated; derivatives or medications based on the carbazole moiety are one of the key contributors. Therefore, this review explores carbazole-based derivatives as possible drugs to treat Alzheimer's, diabetes, inflammation, cancer, and many more, along with their synthetic schemes, SARs, and activity. Some of the carbazole-based drugs available in the market and under clinical trials are also tabulated. By integrating this insight, describe how these compounds are being reinvented as targeted therapeutic agents. This comprehensive analysis is designed to guide researchers in developing next-generation drugs to address various challenges and leverage the unique pharmacological properties of carbazole-derived drugs.},
}

@article {pmid40908201,
year = {2025},
author = {Jung, JH and Kong, N and Lee, S and , },
title = {Pulse pressure as a predictor of Alzheimer's disease biomarkers and cognitive decline: The moderating role of APOE ε4.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {},
number = {},
pages = {100363},
doi = {10.1016/j.tjpad.2025.100363},
pmid = {40908201},
issn = {2426-0266},
abstract = {BACKGROUND: Elevated pulse pressure (PP), indicative of arterial stiffness, has been implicated in cognitive impairment and Alzheimer's disease (AD) pathology. However, its role in preclinical AD and interactions with genetic risk factors like apolipoprotein E ε4 (APOE4) remain unclear.

OBJECTIVES: To investigate the association between baseline PP and AD biomarkers (amyloid-beta (Aβ) and tau) and cognitive decline, and to determine whether APOE4 carrier status moderates these relationships.

DESIGN: Prospective cohort study and secondary analysis of the Anti-Amyloid Treatment in Asymptomatic Alzheimer's (A4) randomized clinical trial SETTING: Multicenter observational cohort and randomized clinical trial conducted at 67 sites across the United States, Canada, Australia, and Japan.

PARTICIPANTS: This study included 1690 cognitively unimpaired older adults from the A4 and Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) studies. Participants underwent baseline PP assessment, Aβ and tau PET imaging, and cognitive testing with longitudinal follow-up over 240 weeks.

MEASUREMENTS: Blood pressure was measured at baseline, with PP calculated as the difference between systolic and diastolic pressures. AD pathologies were assessed through Aβ PET imaging using 18F-Florbetapir, and regional tau deposition in inferior temporal and meta-temporal regions using 18F-Flortaucipir PET imaging. Cognitive performance was measured using the Preclinical Alzheimer Cognitive Composite (PACC).

RESULTS: Higher baseline PP was significantly associated with increased Aβ (β = 0.078; p = 0.001), inferior temporal tau (β = 0.110; p = 0.032), and meta-temporal tau deposition (β = 0.116; p = 0.022). In longitudinal analyses, elevated PP predicted greater decline in PACC scores (β = -0.020; p < 0.001). APOE4 status moderated these associations, with significant effects of PP on tau deposition and cognitive decline observed exclusively among APOE4 carriers. Mediation analysis indicated that tau deposition significantly mediated the association between PP and cognitive decline (indirect effect β = -0.068; 95 % CI [-0.126, -0.011]).

CONCLUSIONS: Elevated PP is associated with increased AD biomarker burden and accelerated cognitive decline in cognitively unimpaired older adults, particularly among APOE4 carriers. Our study suggests that arterial stiffness may contribute to AD pathogenesis and progression via tau pathology. These results highlight the potential of vascular health management as an early intervention target for AD prevention, especially in genetically at-risk populations.},
}

@article {pmid40907816,
year = {2025},
author = {Rai, S and Nair, A and Saleem, Z and Ray, SK and Kanwar, JR and Mukherjee, S},
title = {Advancing nanotheranostics for neuro-immunological disorders: current status and future prospects.},
journal = {Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuroscience.2025.08.051},
pmid = {40907816},
issn = {1873-7544},
abstract = {Neuroimmunological disorders involve complex interactions between the nervous and immune systems, leading to various severe neurological conditions such as Alzheimer's disease, Parkinson's disease, and multiple sclerosis. These disorders are characterized by immune-mediated damage or inflammation within nervous tissue, resulting in cognitive deficits, movement issues, sensory impairments, and other neurological problems. They can affect people of all ages, but incidence increases significantly with advancing age, making them a growing public health concern. As the global population ages, the prevalence of neuroimmunological diseases is expected to rise sharply. Projections indicate that by 2050, approximately 150 million individuals worldwide may suffer from dementia-related disorders alone, with an economic burden reaching around $10 trillion. Current therapies mainly focus on symptom management, aiming to slow disease progression and improve quality of life. Emerging therapeutic strategies show promise, particularly nanomedicine, which employs nanoscale materials to deliver drugs precisely to affected tissues. This targeted approach reduces side effects and increases treatment effectiveness. Additionally, natural products and plant-based compounds are gaining attention for their neuroprotective effects, as they can modulate pathways involved in neuronal survival, repair, and immune regulation. Future research aims to deepen understanding of the molecular and genetic mechanisms underlying these disorders through advanced experimental models and technologies. These insights will facilitate the development of innovative therapies targeting neuroinflammation and immune dysregulation, with the goal of preventing disease progression or even achieving cures. Continued progress in neuroimmunology offers hope for improved treatment outcomes, reduced disease burden, and transformative advances in neurological healthcare worldwide.},
}

@article {pmid40907613,
year = {2025},
author = {Li, K and Qiu, X and Yang, Q and Wang, Z},
title = {Histone modifications: Key players in Alzheimer's disease.},
journal = {Mechanisms of ageing and development},
volume = {},
number = {},
pages = {112102},
doi = {10.1016/j.mad.2025.112102},
pmid = {40907613},
issn = {1872-6216},
abstract = {Alzheimer's disease (AD) is one of the most prevalent diseases in the older population. AD causes progressive cognitive and behavioral impairment, but current treatments are unable to slow or prevent the progression of this disease. Thus, identification of novel biomarkers and therapeutic targets is urgently needed. We previously described the roles of histone acetylation, crotonylation, and lactylation in the accumulation of amyloid beta and hyperphosphorylation of Tau protein, which are the hallmarks of AD. In this review, we summarize and discuss the current knowledge of the role of histone modifications in AD, with a particular emphasis on its association with characterized pathological alterations, including amyloid plaques, Tau tangles, neuroinflammation, and synaptic dysfunction. This review provides novel insights into the central role of histone modifications in AD pathogenesis and evaluates histone-modifying enzymes as potential therapeutic targets for the treatment of AD.},
}

@article {pmid40907541,
year = {2025},
author = {Wu, N and Wu, Z and Wang, P and Zhang, C and Wu, C and Huo, X and Zhang, G},
title = {Three-Dimensional Magnetic Field Measurement of Transcranial Magnetic Stimulation Using a Printed Circuit Board-Based Miniature Orthogonal Coil Array.},
journal = {Biomedical physics & engineering express},
volume = {},
number = {},
pages = {},
doi = {10.1088/2057-1976/ae0340},
pmid = {40907541},
issn = {2057-1976},
abstract = {OBJECTIVE: Transcranial magnetic stimulation (TMS) is a promising neuromodulation therapy for treating diseases such as depression and Alzheimer's disease. However, its efficacy depends on precise magnetic field targeting. Current measurement methods face a trade-off between accuracy and complexity. Their intricate designs limit miniaturization, and they are typically confined to one-dimensional detection.

APPROACH: This study proposes a miniaturized printed circuit board (PCB)-integrated coil array (11.10 mm × 9.10 mm × 1.60 mm) as a novel solution to replace complex probe systems for the synchronous measurement of three-dimensional magnetic field components (Bx, By, Bz) generated by a figure-8 coil.

RESULTS: Using this approach, we simulated and measured the magnetic field distribution produced by a self-made figure-8 coil, demonstrating consistency with relative errors below 5%, 10%, and 15% along the line of interest (LOI) in the x, y, z directions, respectively. Variations in magnetic flux density from a commercial figure-8 coil were also measured at two specific spatial positions, showing consistent trends.

SIGNIFICANCE: The presented measurement probe enables feasible characterization of TMS-induced magnetic flux, with measured values aligning closely with simulated results. By integrating orthogonal coils into a compact PCB, it overcomes the traditional accuracy-complexity trade-off. Clinically, it assists in precise coil positioning during treatment, reducing off-target side effects via magnetic field validation. Technologically, its compact and cost-effective design accelerates testing of novel TMS coils, advancing the development of efficient neuromodulation devices.},
}

@article {pmid40906916,
year = {2025},
author = {Kakoty, V and Kang, JH and Lee, OH and Oh, DH and Ko, YT},
title = {Grueneberg Ganglion: An Unexplored Site for Intranasal Drug Delivery in Alzheimer's Disease.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.5c00376},
pmid = {40906916},
issn = {1948-7193},
abstract = {Neurological disorders such as Alzheimer's Disease, Parkinson's Disease, Huntington's Disease, Multiple Sclerosis, and Amyotrophic Lateral Sclerosis pose significant challenges for treatment. Reasons for the difficulty in finding cures for these conditions include complications in early diagnosis, progressive and irreversible neuronal damage, and the presence of the blood-brain barrier (BBB), which hinders the delivery of drugs to the affected areas of the brain. Intranasal (INL) drug administration has increasingly gained popularity among researchers for targeting neurological conditions, because of its ability to bypass the BBB. However, chronic INL administration leads to nasal mucosa irritation. Additionally, rapid mucociliary clearance, a lack of targeted drug delivery, increased enzymatic degradation, and tight junctions that obstruct drug transport limit the clinical applicability of the INL route. To overcome these challenges, a unique region in the rodent nose, known as the Grueneberg Ganglion (GG), can be considered to be a novel site for INL drug administration. GG is a small structure housed under the snout cartilage of the nasal septum, approximately 1.5 mm from the nasal opening in mice. It is directly connected to the main olfactory bulb through axons. This Perspective aims to expand knowledge on why GG may be a viable option for INL delivery to combat neurological conditions. For better understanding, we have explained the INL administration in GG, using Alzheimer's Disease and INL insulin therapy as a role model for the current review.},
}

@article {pmid40904621,
year = {2025},
author = {Castilhos, RM and Formoso, CR and Borelli, WV and Teixeira, EC and Dousseau, GC and Chaves, MLF and Brucki, SMD},
title = {Anticholinergic burden and polypharmacy in patients referred from primary care to tertiary dementia centers in Brazil.},
journal = {Dementia & neuropsychologia},
volume = {19},
number = {},
pages = {e20240246},
pmid = {40904621},
issn = {1980-5764},
abstract = {UNLABELLED: Anticholinergic burden (ACB) and polypharmacy are poorly studied in the context of primary care in Brazil.

OBJECTIVE: To evaluate the ACB and polypharmacy of individuals with suspected dementia referred from primary care to tertiary dementia outpatient clinics in Brazil.

METHODS: We performed a cross-sectional study in two tertiary dementia clinics. We included individuals with suspected dementia referred from primary care. Sociodemographic variables, number of drugs, ACB score, disease duration, Mini Mental State Examination (MMSE) were collected in the first evaluation. Final diagnosis received was also collected.

RESULTS: A total of 921 individuals were included, with a median (IQR) age of 72 [64-78] years, 57.8% (532) women, 4 [2-7] years of formal education and 15 [10-20] points in MMSE. Most patients had a final diagnosis of dementia (66%, 616) and Alzheimer's disease (21.4%, 197), psychiatric disorders (16%, 147) and multifactorial dementia (14.8%, 136) were the most common diagnoses. Most individuals (68.1%, 627) were using at least one medication with anticholinergic effect, and in 44.6% (411) there was polypharmacy. ACB total score correlated with MMSE (rho=-0.13) and with total number of medications (rho=0.52). In multivariate regression, ACB score ≥1 was associated with MMSE and polypharmacy.

CONCLUSION: Most individuals referred from primary care in Brazil were using at least one medication with anticholinergic effect and this was correlated with cognitive severity. Educational measures for primary care physicians, focusing on the management of pharmacological treatment, are essential to reduce the anticholinergic load in this context.},
}

@article {pmid40904419,
year = {2025},
author = {Mullins, GR and Ardayfio, P and Gueorguieva, I and Anglin, G and Bailey, J and Chua, L and Zimmer, JA and Evans, CD and Nery, ESM and Wang, H and Khanna, R and Brooks, DA and Sims, JR},
title = {Donanemab immunogenicity in participants with early symptomatic Alzheimer's disease.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {11},
number = {3},
pages = {e70149},
pmid = {40904419},
issn = {2352-8737},
abstract = {INTRODUCTION: Donanemab is an immunoglobulin G1 antibody that targets an N-terminal truncated form of amyloid beta present in mature plaques. Treatment-emergent (TE) anti-drug antibodies (ADAs) were quantified in donanemab-treated participants from two pivotal clinical trials, and effects of TE ADAs on donanemab pharmacokinetics, efficacy, and safety were assessed.

METHODS: Data were pooled from the phase 2 TRAILBLAZER-ALZ (NCT03367403) and phase 3 TRAILBLAZER-ALZ 2 trials (NCT04437511). Eligible participants were randomized 1:1 to donanemab (700 mg for the first three doses, 1400 mg thereafter) or placebo intravenously every 4 weeks up to 72 weeks. TE ADA-evaluable participants had a non-missing baseline ADA result and ≥ 1 non-missing post-baseline ADA result. TE ADA incidence and effect of titer on pharmacokinetics, amyloid plaque reduction, clinical efficacy (measured by change from baseline of integrated Alzheimer's Disease Rating Scale [iADRS] score and Clinical Dementia Rating Scale Sum of Boxes [CDR-SB]), and safety were assessed.

RESULTS: Of 922 TE ADA-evaluable donanemab-treated participants, 56 (6.1%) had ADAs detected at baseline, and 812 (88.1%) were TE ADA positive. Donanemab clearance increased linearly with logarithm of ADA titer; however, titer did not affect maximum donanemab concentration. Amyloid plaque level was significantly reduced with donanemab versus placebo, irrespective of titer (P < 0.001 for all). No association was found between ADA presence or titer and donanemab efficacy by iADRS or CDR-SB. Eighty-four of 984 (8.5%) donanemab-treated participants and 4 of 999 (0.4%) placebo-treated participants reported infusion-related reactions (IRRs). All donanemab-treated participants reporting immediate IRRs developed ADAs at some point during the study; however, 90.5% of TE ADA-positive participants did not experience IRRs.

DISCUSSION: Most participants were TE ADA positive. TE ADAs increased donanemab clearance but did not have clinically meaningful impact on plaque reduction or efficacy. While all participants reporting IRRs developed ADAs at some point during the study, the majority of participants with ADAs did not experience IRRs.

HIGHLIGHTS: In pivotal trials, most donanemab-treated participants were treatment-emergent anti-drug antibody (TE ADA) positive.TE ADAs increased donanemab clearance but did not impact plaque reduction/efficacy.All participants reporting infusion-related reactions (IRRs) developed ADAs at some point during the study.However, the majority of participants with ADAs did not experience IRRs.},
}

@article {pmid40904199,
year = {2025},
author = {Isik, S and Osman, S and Yeman-Kiyak, B and Shamshir, SRM and Sanchez, NME},
title = {Advances in Neurodegenerative Disease Therapy: Stem Cell Clinical Trials and Promise of Engineered Exosomes.},
journal = {CNS neuroscience & therapeutics},
volume = {31},
number = {9},
pages = {e70577},
doi = {10.1111/cns.70577},
pmid = {40904199},
issn = {1755-5949},
mesh = {Humans ; *Exosomes/transplantation/metabolism ; *Neurodegenerative Diseases/therapy ; Animals ; *Stem Cell Transplantation/methods/trends ; *Clinical Trials as Topic/methods ; },
abstract = {AIM: This review provides a systematic evaluation of 94 stem cell clinical trials to treat neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease.

METHODS: Data were collected from using relevant search terms, focusing exclusively on stem cell therapy. Of the 8000+ participants in these trials, nearly 70% were enrolled in AD-related studies. Only three Phase 3 studies were conducted, and most trials were in the early phases (Phases 1 and 2). Mesenchymal stem cells, neural stem cells, induced pluripotent stem cells, and embryonic stem cells are used the most to treat neurodegenerative diseases. This review also explores the emerging fields of preclinical and clinical investigations of stem cell-derived exosome-based therapies for neurodegenerative diseases.

RESULTS: Exosomes can cross the blood-brain barrier to deliver therapeutic molecules directly to the brain, offering a less invasive alternative to stem cell transplantation. Mesenchymal stem cell-derived exosomes, in particular, have demonstrated significant potential in preclinical models by reducing neuroinflammation, oxidative stress, and promoting neuronal regeneration. Additionally, recent advances in exosome engineering, including surface modifications, therapeutic agent loading, and transgenic modifications, have improved targeting, stability, blood-brain barrier delivery, and neural cell interactions, enabling targeted and effective treatment. Exosome-based therapies are in the preliminary phases of clinical investigation, with only three clinical trials.

CONCLUSION: Given the increasing interest in exosome therapy, clinical investigations are expected to increase. This growth will be driven by ongoing advancements in exosome technology, a deeper understanding of their therapeutic potential, and escalating demand for innovative treatment strategies for neurodegenerative diseases.},
}

Humans
*Exosomes/transplantation/metabolism
*Neurodegenerative Diseases/therapy
Animals
*Stem Cell Transplantation/methods/trends
*Clinical Trials as Topic/methods

@article {pmid40904091,
year = {2025},
author = {Hu, WQ and Gao, HY and Yang, L and Wang, YX and Cheng, HJ and Yang, SY and Zhang, MY and Sun, J},
title = {[Characterization of hippocampal components of Danzhi Xiaoyao Formula based on HPLC-Q-TOF-MS/MS and network pharmacology and assessment of its therapeutic potential for nervous system diseases].},
journal = {Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica},
volume = {50},
number = {14},
pages = {4053-4062},
doi = {10.19540/j.cnki.cjcmm.20250426.201},
pmid = {40904091},
issn = {1001-5302},
mesh = {*Drugs, Chinese Herbal/chemistry/administration & dosage ; Animals ; Rats ; *Hippocampus/drug effects/chemistry/metabolism ; Network Pharmacology ; Chromatography, High Pressure Liquid ; Tandem Mass Spectrometry ; Rats, Sprague-Dawley ; Male ; *Nervous System Diseases/drug therapy/metabolism/genetics ; Humans ; Signal Transduction/drug effects ; },
abstract = {In this study, the pharmacodynamic components and potential pharmacological functions of Danzhi Xiaoyao Formula in treating nervous system diseases were investigated by hippocampal component characterization and network pharmacology. After rats were administrated with Danzhi Xiaoyao Formula by gavage, high performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry(HPLC-Q-TOF-MS/MS) was employed to explore the components in the hippocampus of rats. Fifty-seven components were identified in the hippocampus of rats by comparing the extract of Danzhi Xiaoyao Formula, herbal components in the hippocampus after administration, and blank samples. KEGG and GO analyses predicted 74 core targets including GSK3B, MAPK1, AKT, IL6. These targets were involved in PI3K/Akt, NF-κB, MAPK, JAK/STAT, Wnt, and other signaling pathways. The results indicated that Danzhi Xiaoyao Formula may ameliorate other nervous system diseases enriched in DO, such as neurodegenerative diseases, cerebrovascular diseases, and mental and emotional disorders by mediating target pathways, inhibiting inflammation, reducing neuronal damage, and alleviating hippocampal atrophy. The relevant activities exhibited by this formula in nervous system diseases such as Alzheimer's disease, Parkinson's disease, and diabetic neuropathy have extremely high development value and are worthy of further in-depth research. This study provides a theoretical basis and practical guidance for expanding the application of Danzhi Xiaoyao Formula in the treatment of nervous system diseases.},
}

*Drugs, Chinese Herbal/chemistry/administration & dosage
Animals
Rats
*Hippocampus/drug effects/chemistry/metabolism
Network Pharmacology
Chromatography, High Pressure Liquid
Tandem Mass Spectrometry
Rats, Sprague-Dawley
Male
*Nervous System Diseases/drug therapy/metabolism/genetics
Humans
Signal Transduction/drug effects

@article {pmid40904084,
year = {2025},
author = {Pu, YZ and Chen, HF and Wang, XY and Su, C},
title = {[Caffeoylquinic acids from Erigeron breviscapus ameliorates cognitive impairment and mitochondrial dysfunction in AD by activating PINK1/Parkin-mediated mitophagy].},
journal = {Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica},
volume = {50},
number = {14},
pages = {3969-3979},
doi = {10.19540/j.cnki.cjcmm.20250219.402},
pmid = {40904084},
issn = {1001-5302},
mesh = {Animals ; *Alzheimer Disease/drug therapy/genetics/metabolism/physiopathology/psychology ; *Mitophagy/drug effects ; *Mitochondria/drug effects/metabolism/genetics ; Caenorhabditis elegans/drug effects/genetics/metabolism ; *Ubiquitin-Protein Ligases/metabolism/genetics ; *Cognitive Dysfunction/drug therapy/metabolism/genetics/physiopathology ; Rats ; *Protein Kinases/metabolism/genetics ; Humans ; Male ; Disease Models, Animal ; Caenorhabditis elegans Proteins/metabolism/genetics ; *Drugs, Chinese Herbal/administration & dosage ; },
abstract = {This study aimed to investigate the effects of caffeoylquinic acids from Erigeron breviscapus(EBCQA) on cognitive impairment and mitochondrial dysfunction in Alzheimer's disease(AD), and to explore its underlying mechanisms. The impacts of EBCQA on paralysis, β-amyloid(Aβ) oligomerization, and mRNA expression of mitophagy-related genes [PTEN-induced putative kinase 1(PINK1) homolog-encoding gene pink-1, Parkin homolog-encoding gene pdr-1, Bcl-2 interacting coiled-coil protein 1(Beclin 1) homolog-encoding gene bec-1, microtubule-associated protein 1 light chain 3(LC3) homolog-encoding gene lgg-1, autophagic adapter protein 62(p62) homolog-encoding gene sqst-1] were examined in the AD Caenorhabditis elegans CL4176 model, along with mitochondrial functions including adenosine triphosphate(ATP) content, enzyme activities of mitochondrial respiratory chain complexes Ⅰ,Ⅲ, and Ⅳ, and mitochondrial membrane potential. Additionally, the effects of EBCQA on the green fluorescent protein(GFP)/red fluorescent protein from Discosoma sp.(DsRed) ratio, the expression of phosphatidylethanolamine-modified and GFP-labeled LGG-1(PE-GFP::LGG-1)/GFP-labeled LGG-1(GFP::LGG-1), and GFP-labeled SQST-1(GFP::SQST-1) proteins were investigated in transgenic C. elegans strains. The effect of EBCQA on paralysis was further evaluated after RNA interference(RNAi)-mediated suppression of the pink-1 and pdr-1 genes in CL4176 strain. An AD rat model was established through intraperitoneal injection of D-galactose and intragastric administration of aluminum trichloride. The effects of β-nicotinamide mononucleotide(NMN) and EBCQA on learning and memory ability, neuronal morphology, mitophagy occurrence, mitophagy-related protein expression(PINK1, Parkin, Beclin 1, LC3-Ⅱ/LC3-Ⅰ, p62), and mitochondrial functions(ATP content; enzyme activities of mitochondrial respiratory chain complexes Ⅰ, Ⅲ, and Ⅳ; mitochondrial membrane potential) were investigated in this AD rat model. The results showed that EBCQA delayed paralysis onset in the CL4176 strain, reduced Aβ oligomer formation, and upregulated the mRNA expression levels of lgg-1, bec-1, pink-1, and pdr-1, while downregulating sqst-1 mRNA expression. EBCQA also enhanced ATP content, mitochondrial membrane potential, and the activities of mitochondrial respiratory chain complexes Ⅰ, Ⅲ, and Ⅳ. Furthermore, EBCQA improved the PE-GFP::LGG-1/GFP::LGG-1 ratio, reduced GFP::SQST-1 expression, and decreased the GFP/DsRed ratio. Notably, the ability of EBCQA to delay paralysis was significantly reduced following RNAi-mediated suppression of pink-1 and pdr-1 in CL4176 strain. In AD rats, the administration of NMN or EBCQA significantly improved learning and memory, restored neuronal morphology in the hippocampus, increased autophagosome numbers, and upregulated the expression of PINK1, Parkin, Beclin 1, and the LC3-Ⅱ/LC3-Ⅰ ratio, while reducing p62 expression. Additionally, the treatment with NMN or EBCQA both elevated ATP content, mitochondrial respiratory chain complex Ⅰ, Ⅲ, and Ⅳ activities, and mitochondrial membrane potential in the hippocampus. The above findings indicate that EBCQA improves cognitive impairment and mitochondrial dysfunction in AD, possibly through activation of PINK1/Parkin-mediated mitophagy.},
}

Animals
*Alzheimer Disease/drug therapy/genetics/metabolism/physiopathology/psychology
*Mitophagy/drug effects
*Mitochondria/drug effects/metabolism/genetics
Caenorhabditis elegans/drug effects/genetics/metabolism
*Ubiquitin-Protein Ligases/metabolism/genetics
*Cognitive Dysfunction/drug therapy/metabolism/genetics/physiopathology
Rats
*Protein Kinases/metabolism/genetics
Humans
Male
Disease Models, Animal
Caenorhabditis elegans Proteins/metabolism/genetics
*Drugs, Chinese Herbal/administration & dosage

@article {pmid40903965,
year = {2025},
author = {Parikh, A and Cholavaram, A and Chitti Babu, AK and Deepankumar, K and Vijayan, M},
title = {Role of voltage-dependent anion channel 1 in neurodegeneration: Mechanisms, implications, and therapeutic potential.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRR-D-25-00368},
pmid = {40903965},
issn = {1673-5374},
abstract = {Voltage-dependent anion channel 1 is an integral outer membrane protein of the mitochondria that governs apoptosis, enables metabolite exchange, and influences mitochondrial activity. In neurodegenerative diseases, such as amyotrophic lateral sclerosis, Parkinson's disease, Huntington's disease, and Alzheimer's disease, oxidative stress, neuroinflammation, and mitochondrial dysfunction are frequent features. Voltage-dependent anion channel 1 is a key regulator of these processes. This review described the structure, membrane topology, and physiological function of voltage-dependent anion channel 1 in neurons and glial cells. We emphasize how it affects mitophagy, oxidative damage, and changes in mitochondrial permeability. Special attention is focused on how voltage-dependent anion channel 1 interacts with pathogenic proteins that damage mitochondrial integrity and cause neurotoxicity, including mutant huntingtin, phosphorylated tau, α-synuclein, amyloid-beta, and TAR DNA-binding protein 43. Furthermore, the paper examines the function of voltage-dependent anion channel 1 in astrocytic dysfunction and microglial activation, highlighting its impact on neuroinflammation. In a nutshell, we assess treatment strategies that target voltage-dependent anion channel 1, such as VBIT-4, a selective inhibitor of voltage-dependent anion channel 1 oligomerization, and newer methods, including structure-based drug design and CRISPR/Cas9 regulation. Improved knowledge of the hinter voltage-dependent anion channel 1 of the molecular mechanism may allow for new therapeutic approaches in neurodegenerative diseases.},
}

@article {pmid40903964,
year = {2025},
author = {Wu, S and Guo, T and Zheng, X and Gu, C and Hu, Y and Gu, X and Zhou, X},
title = {Integrated machine learning-based RNA sequencing and single-cell analysis reveal RNA methylation regulation patterns in the immune microenvironment of Alzheimer's disease.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRR-D-24-01650},
pmid = {40903964},
issn = {1673-5374},
abstract = {Alterations in RNA methylation may affect the initiation and development of Alzheimer's disease. However, the exact nature of the relationship between RNA methylation and Alzheimer's disease remains unclear. In this study, RNA methylation levels were analyzed by bulk transcriptomic and single-cell RNA sequencing. The expression levels of RNA methylation regulators were confirmed using molecular biology techniques. Co-expression network analysis was used to identify relevant long non-coding RNAs. Molecular subtypes related to RNA methylation were classified, and variations in clinical characteristics, biological behavior, and immune signatures between subtypes were assessed. Machine learning approaches were applied to identify methylation-associated long noncoding RNAs, which were used to construct a risk model and nomogram for Alzheimer's disease. Potential therapeutic agents for different risk groups were predicted, and in vitro experiments were conducted to identify key RNA methylation events. Single-cell analysis demonstrated enhanced RNA methylation in patients with Alzheimer's disease, particularly within T cells, B cells, and NK cells. Quantitative reverse transcription-polymerase chain reaction and western blot confirmed alterations in RNA methylation regulators in neurons treated with amyloid-β oligomers in vitro. This evidence supported the classification of patients with Alzheimer's disease into heterogeneous subtypes. Specifically, subtype 1 was identified as the immune-active subtype, while subtype 2 was characterized by a metabolic phenotype. Machine learning algorithms identified five significant methylation-associated long non-coding RNAs -LINC01007, MAP4K3-DT, MIR302CHG, VAC14-AS1, and TGFB2-OT1-that accurately predict clinical outcomes for patients with Alzheimer's disease. These patients were classified into low- and high-risk categories; the latter group displayed higher immune infiltration, upregulated immune regulatory gene expression, and elevated immune scores and responded better to treatment with arachidonic-trifluoroethane. These findings suggest that dysregulated RNA methylation alters the immune microenvironment in Alzheimer's disease and is closely associated with its progression. This phenomenon provides novel insights into potential therapeutic strategies for Alzheimer's disease that target RNA methylation.},
}

@article {pmid40903963,
year = {2025},
author = {Fan, F and Zhao, N and Guo, M},
title = {Lymphatic-venous anastomosis: Cracking the code of Alzheimer's disease treatment?.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRR-D-25-00540},
pmid = {40903963},
issn = {1673-5374},
}

@article {pmid40903956,
year = {2025},
author = {Chen, Y and Yin, P and Chen, Q and Zhang, Y and Tang, Y and Jin, W and Yu, L},
title = {Neurodegenerative diseases and immune system: From pathogenic mechanism to therapy.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRR-D-25-00274},
pmid = {40903956},
issn = {1673-5374},
abstract = {Neurodegenerative diseases are a class of disorders with the gradual loss of the central nervous system and peripheral nervous system. Neurodegenerative diseases manifest primarily as cognitive and behavioral disorders that adversely affect the lives of millions of people worldwide. Therefore, it is necessary to elucidate the mechanism of neurodegenerative diseases further and find effective new therapies. In recent years, increasing evidence has shown that the immune system plays a significant role in the pathophysiology of neurodegenerative diseases and regulates this process. The central and peripheral immune systems exert different roles in the disease progression. The development of neurodegenerative diseases is influenced by interactions between them. This review focuses on how the immune system, including microglia mediated nucleotide-binding oligomerization domainlike receptor protein 3 inflammation activation and T cell-mediated neuroinflammation, interactions with neurodegenerative diseases by modulating protein aggregation and blood-brain barrier permeability. Besides, we gave particular attention to glial cell-centered multicellular interactions and the inflammatory signaling pathway. Insight into the immune system's functions and cellular interactions is essential for progressing disease research. In addition, the functions and mechanisms of these immune cells also suggest new ideas and targets for treatment. Therefore, this review summarizes some of the existing treatment strategies for amyloid-beta, tau, neuroinflammation, α-synuclein, associated microbiota, immune modulation, and neural injury repair. In addition, this review summarizes and compares animal models of different common neurodegenerative diseases and clinical research progress. In view of the current research status, new research directions and suggestions are proposed.},
}

@article {pmid40903950,
year = {2025},
author = {Liu, Y and Tang, T and Cai, H and Liu, Z},
title = {Bidirectional communication between the gut microbiota and the central nervous system.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRR-D-25-00434},
pmid = {40903950},
issn = {1673-5374},
abstract = {In recent years, an increasing number of researchers have become interested in the bidirectional communication between the gut microbiota and the central nervous system. This communication occurs through the microbiota-gut-brain axis. As people age, the composition of the gut microbiota undergoes considerable changes, which are now known to play an important role in the development of many neurodegenerative diseases. This review aims to investigate the complex bidirectional signaling pathways between the gut and the brain. It summarizes the latest research findings on how the gut microbiota and its metabolites play critical roles in regulating inflammation, maintaining gut health, and influencing the development of neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. The review also analyzes the current clinical applications of gut microbiota-based treatments for neurological disorders, including fecal microbiota transplantation, probiotics, and prebiotics. Many studies show that the gut microbiota affects the brain in several ways. For example, it can produce substances such as short-chain fatty acids and activate inflammatory pathways. Studies involving animals and laboratory models have demonstrated that adjusting the gut microbiota can help improve behavior and reduce neurological problems. Recent metagenomic and metabolomics studies have shown that the microbiota plays a crucial role in maintaining the organism's health. Microorganisms primarily colonize the gut and are involved in host nutrient metabolism, maintaining the structural integrity of the intestine, preserving the intestinal mucosal barrier, and modulating the immune system. The gut microbiota communicates with the brain through a bidirectional microbiota-gut-brain axis. The composition of the gut flora changes considerably with age, and ecological dysregulation has been recognized as one of the twelve most recent hallmarks of aging. Recent studies have linked these changes to a variety of age-related neurological disorders, including Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, multiple sclerosis, and Huntington's disease. Specifically, the gut microbiota influences the brain through the production of key metabolites such as short-chain fatty acids and the activation of inflammatory and other relevant signaling pathways. In preclinical studies, targeted modulation of the gut microbiota, through methods such as fecal microbiota transplantation, probiotics, and prebiotics, has demonstrated potential in improving host behavioral outcomes. Therefore, gut microbiotabased treatments offer new hope for the treatment of nervous system diseases. However, due to the complexity of the gut microbiota and the potential adverse reactions associated with these therapies, researchers need to carefully assess their safety and efficacy before widespread clinical application.},
}

@article {pmid40903895,
year = {2025},
author = {Higgins, A and Tewolde, S and Page, SD and Rubenstein, E},
title = {The Occurrence of Obstructive Sleep Apnea and Its Association With Alzheimer Dementia in Medicaid-Enrolled Adults With Down Syndrome, 2011-2019.},
journal = {American journal of medical genetics. Part A},
volume = {},
number = {},
pages = {e64241},
doi = {10.1002/ajmg.a.64241},
pmid = {40903895},
issn = {1552-4833},
support = {R01AG073179/AG/NIA NIH HHS/United States ; },
abstract = {Down syndrome is a condition caused by trisomy of chromosome 21 and is the most common genetic cause of intellectual disability. Due to distinct body and facial morphology, people with Down syndrome appear to be at increased risk for obstructive sleep apnea (OSA). Additionally, adults with Down syndrome are at increased risk for Alzheimer dementia at younger ages than the general population, and OSA has been identified as a risk factor for Alzheimer dementia in the general population. This study aims to explore the prevalence of diagnosed OSA, as well as the association between OSA and Alzheimer dementia, in adults with Down syndrome using Medicaid claims data from2011 to 2019. Of 118,539 adults with Down syndrome who met inclusion criteria, 23,785 had at least one OSA claim from2011 to 2019 (20.1%, 95% CI 19.8%-20.3%). After weighting for age, sex, dual enrollment, race, ethnicity, and region, adults with Down syndrome and OSA claims had 1.08 times the hazard of having a claim for Alzheimer dementia compared to those without OSA claims (95% CI 1.05-1.10). OSA is common in adults, and our findings have clinical implications for its evaluation and treatment in those with Down syndrome.},
}

@article {pmid40903623,
year = {2025},
author = {Anzai, Y and Minoshima, S},
title = {The role of brain MR and FDG-PET in the diagnosis of neurodegenerative disease.},
journal = {European radiology},
volume = {},
number = {},
pages = {},
pmid = {40903623},
issn = {1432-1084},
abstract = {Alzheimer disease (AD) is the most common dementing disorder, affecting 55 million people worldwide. Brain MRI plays an integral role in the diagnostic evaluation of patients with cognitive symptoms. When interpreting brain MRI for cognitive impairment, radiologists should assess the following four key features: (1) white matter ischemic burden, (2) structural changes to suggest normal pressure hydrocephalus, (3) locoregional pattern of brain atrophy, and (4) presence of microhemorrhage or superficial siderosis, particularly for determining eligibility for anti-amyloid monoclonal antibody (MAB) treatment when appropriate. The recent approval and clinical adoption of anti-amyloid MAB expanded the role of neuroradiologists in evaluating eligibility and monitoring ARIA (amyloid-related imaging abnormality) among patients receiving anti-amyloid MAB. This advancement underscores the importance of standardized imaging protocols and effective communication between neuroradiologists and cognitive neurologists. Depending on the severity of ARIA and patients' symptoms, treatment may need to be suspended or discontinued. This review article explores brain MRI and FDG-PET/CT imaging abnormalities in patients with major cognitive and movement disorders associated with dementia. It aims to assist radiologists in providing differential diagnoses within a clinical context. Finally, the article emphasizes the importance of recognizing co-pathologies, since patients may have more than one neurodegenerative disease rather than viewing these neurodegenerative diseases as being mutually exclusive. KEY POINTS: Question Traditional regional patterns of brain atrophy on MRI by neuroradiologists may not be effective given the recent advances in understanding of neurodegenerative disease and recognition of co-pathologies. Findings The locoregional atrophy and the patterns of metabolic abnormality help in the differential diagnosis of neurodegenerative disease. Remember that brain MRI determines eligibility for anti-amyloid immunotherapy. Clinical relevance Understanding clinical history is vital for interpreting brain MRI for patients with cognitive impairment or memory loss. Newly recognized entities such as limbic-predominant age-related TDP43 encephalopathy (LATE) can mimic Alzheimer disease among extremely elderly patients with amnestic symptoms with mesial temporal lobe atrophy.},
}

@article {pmid40903613,
year = {2025},
author = {Horn, A and Neumann, WJ},
title = {From adaptive deep brain stimulation to adaptive circuit targeting.},
journal = {Nature reviews. Neurology},
volume = {},
number = {},
pages = {},
pmid = {40903613},
issn = {1759-4766},
abstract = {Deep brain stimulation (DBS) substantially improves motor symptoms and quality of life in people with movement disorders such as Parkinson disease and dystonia, and it is also being explored as a treatment option for other brain disorders, including treatment-resistant obsessive-compulsive disorder, Alzheimer disease and depression. Two major developments are currently driving progress in DBS research: first, the framework of adaptive DBS, which senses brain activity to infer the momentary state of the symptoms of a patient and reacts by adapting stimulation settings, and second, the concept of connectomic DBS, which identifies brain circuits that should optimally be stimulated to reduce specific symptoms. In this Perspective, we propose a unified framework that combines these two concepts. Our approach, termed adaptive circuit targeting, decodes symptom severity from brain signals and adaptively activates the most relevant symptom-response circuits. We discuss the state of the art in the adaptive and connectomic DBS fields and the research gaps that need to be addressed to unify these concepts.},
}

@article {pmid40903459,
year = {2025},
author = {Zhang, B and Zhang, S and Guo, Z and Hong, C and Zhang, F and Lin, H},
title = {Nesfatin-1 ameliorates blood-brain barrier dysfunction in Alzheimer's disease by targeting VEGF-R1 and reducing cellular senescence in brain vascular endothelial cells.},
journal = {Translational psychiatry},
volume = {15},
number = {1},
pages = {341},
pmid = {40903459},
issn = {2158-3188},
mesh = {Animals ; *Blood-Brain Barrier/metabolism/drug effects/physiopathology ; *Nucleobindins/metabolism ; *Cellular Senescence/drug effects ; *Alzheimer Disease/metabolism/physiopathology ; Mice ; *Endothelial Cells/metabolism/drug effects ; Amyloid beta-Peptides/metabolism ; Peptide Fragments ; Brain/metabolism ; Mice, Transgenic ; Male ; Disease Models, Animal ; Humans ; },
abstract = {Cellular senescence and associated endothelial permeability are crucial factors in the dysfunction of the blood-brain barrier (BBB) in neurodegenerative diseases, including Alzheimer's disease (AD). Nesfatin-1 (NF-1), a neuropeptide involved in regulating appetite and energy homeostasis, has not been extensively studied for its pathophysiological role in AD. In this study, we found that NF-1 treatment improved cellular senescence in brain vascular endothelial bEnd.3 cells by restoring the expression of hTERT and TERF2 against oligomerized Aβ1-42. Additionally, NF-1 reduced p53 and p21 protein levels in bEnd.3 cells exposed to oligomerized Aβ1-42. Notably, NF-1 reduced oligomerized Aβ1-42-induced endothelial monolayer permeability by maintaining transendothelial electric resistance (TEER) and the levels of tight junction proteins claudin 5 and ZO-1. Furthermore, NF-1 suppressed the expression of VEGF-R1 but not VEGF-R2 in bEnd.3 cells exposed to oligomerized Aβ1-42. Overexpression of VEGF-R1 negated the protective effects of NF-1 against oligomerized Aβ1-42-induced cellular senescence and increased endothelial monolayer permeability, indicating the involvement of VEGF-R1 in this process. Using a transgenic (Tg APPswe/PSEN1dE9) AD mouse model, we demonstrated that NF-1 administration lowered VEGF-R1 expression in the brain cortex of AD mice. Moreover, NF-1 mitigated BBB dysfunction and enhanced the expression of claudin 5 and ZO-1 in the brains of AD mice. Our results suggest that NF-1 may be a potential therapeutic strategy for treating AD.},
}

Animals
*Blood-Brain Barrier/metabolism/drug effects/physiopathology
*Nucleobindins/metabolism
*Cellular Senescence/drug effects
*Alzheimer Disease/metabolism/physiopathology
Mice
*Endothelial Cells/metabolism/drug effects
Amyloid beta-Peptides/metabolism
Peptide Fragments
Brain/metabolism
Mice, Transgenic
Male
Disease Models, Animal
Humans

@article {pmid40902672,
year = {2025},
author = {Sharma, S and Bashir, B and Kolekar, KA and Acharya, A and Gupta, M and Jena, R and Vishwas, S and Kaur, J and Gupta, G and Kumbhar, PS and Patle, D and Chaitanya, M and Gulati, M and Singh, SK},
title = {Tailoring the biomarkers of Alzheimer's disease using a gut microbiome-centric approach: Preclinical, clinical, and regulatory perspectives.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {102888},
doi = {10.1016/j.arr.2025.102888},
pmid = {40902672},
issn = {1872-9649},
abstract = {Alzheimer's disease (AD), a progressive neurodegenerative disorder, poses significant therapeutic challenges due to its complex etiology and limited treatment options. Traditional pharmacotherapies targeting amyloid-β (Aβ) and cholinergic pathways offer modest benefits and are often associated with adverse effects. Emerging evidence implicates gut dysbiosis and the gut-brain axis in the pathogenesis and progression of AD. This review explores the multifactorial pathophysiology of AD and evaluates the therapeutic potential of gut-based interventions such as probiotics, prebiotics, synbiotics, metabiotics, postbiotics, and fecal microbiota transplantation (FMT) in mitigating disease pathology. Emphasis has also been given on role of miRNA released from FMT in management of AD. Preclinical and clinical studies demonstrate that these strategies can restore microbial homeostasis, reduce neuroinflammation, enhance gut barrier integrity, and improve cognitive outcomes. The regulatory aspects with use of probiotics based products and FMT is also highlighted. The modulation of neuroimmune, neuroendocrine, and neural pathways through microbiota-derived metabolites offers a promising avenue for AD management. Despite encouraging findings, further research is needed to address interindividual microbiome variability, delivery challenges, and the requirement for large-scale, randomized trials. Personalized gut-targeted approaches may open new horizons for the prevention and treatment of AD.},
}

@article {pmid40901302,
year = {2025},
author = {Stothart, G and Alderman, S and Hermann, O and Creavin, S and Coulthard, EJ},
title = {A passive and objective measure of recognition memory in mild cognitive impairment using Fastball memory assessment.},
journal = {Brain communications},
volume = {7},
number = {5},
pages = {fcaf279},
doi = {10.1093/braincomms/fcaf279},
pmid = {40901302},
issn = {2632-1297},
abstract = {As viable pharmacotherapies and blood biomarkers emerge for dementia treatment and screening, there remains a great need for accurate, sensitive biomarkers of cognitive function. We have previously demonstrated that Fastball, a new Electroencephalography (EEG) method for the passive and objective measurement of recognition memory that requires no behavioural memory response or task comprehension, is sensitive to cognitive dysfunction in Alzheimer's disease. Here we present new evidence that Fastball is sensitive to amnestic dysfunction in an earlier stage of the dementia lifecourse, Mild Cognitive Impairment (MCI). 53 MCI patients and 54 healthy older adult (HOA) controls completed a 3-min Fastball task in which they passively viewed rapidly presented images while EEG captured their automatic ability to differentiate between images based on previous exposure. They also completed neuropsychological assessments of memory (Delayed Match to Sample-48), sustained attention (Psychomotor Vigilance Task), and general cognitive function (Addenbrookes Cognitive Exam-iii). Participants were re-tested after 1 year to establish the test-retest reliability of Fastball in HOAs, and the sensitivity of Fastball to cognitive decline in MCI patients, over a 1 year period. Amnestic MCI patients showed significantly reduced Fastball responses compared with non-amnestic MCI patients (P = 0.001, Cohen's d = 0.98) and HOA controls (P = 0.005, Cohen's d = 0.64). Regression analyses showed that Fastball EEG responses were selectively predictive of neuropsychological measures of recognition memory and not attention. Between baseline and year one follow-up Fastball showed moderate to good test-retest reliability in HOA controls, and the six MCI-dementia converters showed a trend for lower Fastball responses at baseline which will be confirmed with further longitudinal assessment. Fastball is further validated as a viable method for testing recognition memory in cognitively impaired populations. We have demonstrated that it is selectively predictive of memory dysfunction and not attention or other cognitive functions. It is passive, non-invasive, quick to administer and uses cheap, scalable EEG technology. Fastball is a viable functional biomarker that can help to advance cognitive assessment in MCI.},
}

@article {pmid40899945,
year = {2025},
author = {Saido, TC and Iwata, N},
title = {The tale of donanemab: God is in the details.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251371240},
doi = {10.1177/13872877251371240},
pmid = {40899945},
issn = {1875-8908},
abstract = {Alzheimer's disease is a major cause of dementia, that affects approximately 7-8% of people aged 65 years and older (according to WHO & Alzheimer's Disease International) and thus is a major concern in public health world-wide. This review chronicles the foundational research and translational trajectory leading to the development of donanemab, a monoclonal antibody targeting pyroglutamyl amyloid-β (Aβ3pE-X) peptides, recently approved for the treatment of early Alzheimer's disease (AD). We trace a 30-year arc from the biochemical identification of Aβ species to the recognition of Aβ3pE-42 as a predominant pathological isoform in AD and Down syndrome brains-a fact still underrecognized among clinicians and researchers. We highlight key breakthroughs in antibody generation, Aβ peptide biochemistry, and resistance to enzymatic degradation. Mechanistic distinctions between donanemab (Kisunla[®]), and lecanemab (Leqembi[®]) are also explored, along with therapeutic implications for targeting specific Aβ species at preclinical stages of disease. The review emphasizes how persistent biochemical research, fueled by intellectual curiosity, serendipity, and rigorous experimentation, has culminated in clinical proof-of-concept for the amyloid hypothesis. In addition to its molecular specificity, donanemab's development underscores a critical shift toward precision medicine in Alzheimer's care. Its clinical validation, though limited in scope, reinforces the need for scalable and affordable interventions that can address the growing global burden of dementia. We expect these therapeutic antibodies to contribute to reducing the global burden by ceasing the disease progression in a preclinical stage now that new methods for fluid biomarkers are becoming available. As the global population ages, understanding and addressing AD has become a top priority in neuroscience and public health.},
}

@article {pmid40899340,
year = {2025},
author = {Zamanian, MY and Khachatryan, LG and Heidari, M and Darabi, R and Golmohammadi, M and Al-Aouadi, RFA and Akkol, EK},
title = {The Therapeutic Potential of Flavonols in Alzheimer's Disease: Inhibiting Amyloid-β, Oxidative Stress, and Neuroinflammation.},
journal = {BioFactors (Oxford, England)},
volume = {51},
number = {5},
pages = {e70047},
doi = {10.1002/biof.70047},
pmid = {40899340},
issn = {1872-8081},
mesh = {*Alzheimer Disease/drug therapy/metabolism/pathology/genetics ; Oxidative Stress/drug effects ; *Amyloid beta-Peptides/metabolism/antagonists & inhibitors/genetics ; *Flavonols/pharmacology/therapeutic use ; Animals ; Kaempferols/pharmacology ; Flavonoids/pharmacology ; *Neuroprotective Agents/pharmacology ; Quercetin/pharmacology ; Mice ; Humans ; Male ; Mitochondria/drug effects ; *Neuroinflammatory Diseases/drug therapy ; Signal Transduction/drug effects ; Amyloid Precursor Protein Secretases/genetics/metabolism ; },
abstract = {Alzheimer's disease (AD), a progressive neurodegenerative disorder characterized by amyloid-β (Aβ) aggregation, oxidative stress, and neuroinflammation, remains a significant global health challenge. This study investigates the therapeutic potential of flavonols-quercetin, kaempferol, myricetin, and fisetin-in targeting Aβ aggregation and mitigating AD pathology through diverse molecular mechanisms. Our findings reveal that flavonols effectively inhibit Aβ oligomerization and fibril formation, reduce oxidative stress via Nrf2/HO-1 pathway activation, and suppress neuroinflammation by modulating microglial polarization. Additionally, these compounds enhance mitochondrial function, promote autophagy-mediated clearance of Aβ aggregates, and regulate key enzymes such as β-secretase (BACE1) and α-secretases (ADAM10/17), favoring non-amyloidogenic pathways. Quercetin demonstrated neuroprotective effects by activating TrkB signaling, reducing tau phosphorylation, and enhancing synaptic plasticity. Kaempferol prevented Aβ-induced apoptosis via the ER/ERK/MAPK pathway and inhibited acetylcholinesterase activity, improving cognitive outcomes. Myricetin ameliorated mitochondrial dysfunction and oxidative damage through GSK3β/ERK2 signaling modulation and showed enhanced brain bioavailability when delivered via nanostructured lipid carriers. Fisetin reduced Aβ burden by upregulating neprilysin expression, suppressed neuroinflammation, and improved synaptic function by restoring synaptic protein levels. Overall, flavonols exhibit multi-targeted therapeutic potential against AD by addressing its complex pathogenesis. Their ability to cross the blood-brain barrier and low toxicity profiles position them as promising candidates for further clinical development. This study underscores the potential of flavonols as natural agents for AD treatment and highlights their role in advancing multi-mechanistic therapeutic strategies.},
}

*Alzheimer Disease/drug therapy/metabolism/pathology/genetics
Oxidative Stress/drug effects
*Amyloid beta-Peptides/metabolism/antagonists & inhibitors/genetics
*Flavonols/pharmacology/therapeutic use
Animals
Kaempferols/pharmacology
Flavonoids/pharmacology
*Neuroprotective Agents/pharmacology
Quercetin/pharmacology
Mice
Humans
Male
Mitochondria/drug effects
*Neuroinflammatory Diseases/drug therapy
Signal Transduction/drug effects
Amyloid Precursor Protein Secretases/genetics/metabolism

@article {pmid40898925,
year = {2025},
author = {Park, HA and Amjad, E and Burnett, G and Ferdous, KA and Scott, M and Jansen, J and Bannerman, S and Scott, M and Correll, RN and Ciesla, L and Ellis, A},
title = {Oral Supplementation of Fucoxanthin Regulates Gene Expression in the Brain of Middle-aged Rats.},
journal = {The British journal of nutrition},
volume = {},
number = {},
pages = {1-31},
doi = {10.1017/S0007114525104996},
pmid = {40898925},
issn = {1475-2662},
abstract = {Age is the main risk factor for many neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and frontotemporal dementia. Despite our limited understanding of cellular mechanisms of aging-associated neuronal loss, an increasing number of studies demonstrate that oxidative stress and inflammation are key drivers. Epidemiological studies indicate that diet during middle adulthood can influence the risk of developing neurodegenerative diseases later in life, so it is important to investigate dietary interventions to combat oxidative stress and inflammation. In this study, we hypothesized that treatment with fucoxanthin, a marine carotenoid with strong antioxidant properties, prevents aging-associated oxidative stress that is known to be related to natural brain aging. Treatment with fucoxanthin protected rat primary hippocampal neurons against oxidative stress and aging in vitro. In our in vivo study, middle-aged male Sprague-Dawley rats were gavaged with fucoxanthin (1 mg/kg, 5 days/week, n=6) or vehicle (n=6) for 4 weeks. After supplementation was completed, brain samples were harvested and subjected to quantitative and bioinformatic analyses. Fucoxanthin was detected and shown to decrease lipid peroxidation in the brains of the animals supplemented with fucoxanthin. Microarray analysis showed that treatment with fucoxanthin changed 5602 genes. Together, our results suggest that treatment with fucoxanthin prevents aging-associated oxidative stress and is capable of regulating genes that potentially ameliorate age-related changes to the brain.},
}

@article {pmid40898264,
year = {2025},
author = {Drinkall, NJ and Siersma, V and Lathe, R and Waldemar, G and Janbek, J},
title = {Herpesviruses, antiviral treatment, and the risk of dementia - systematic review and meta-analysis.},
journal = {Alzheimer's research & therapy},
volume = {17},
number = {1},
pages = {201},
pmid = {40898264},
issn = {1758-9193},
mesh = {Humans ; *Antiviral Agents/therapeutic use ; *Dementia/epidemiology/virology ; *Herpesviridae Infections/drug therapy/complications/epidemiology ; *Herpesviridae ; Risk Factors ; },
abstract = {INTRODUCTION: The aim of this systematic review and meta-analysis was to synthesize the evidence on the association between herpesviruses, antiviral treatment, and the risk of dementia. We also aimed to explore the impact of time between herpesviruses and dementia on the reported associations.

METHODS: PubMed and Web of Science were searched along with reference lists of the included studies. We included studies that looked at clinical episodes or serology (IgG/IgM) of herpes simplex virus type 1/2 (HSV1/2) and/or varicella zoster virus (VZV), antiviral treatment and incident dementia (all-cause dementia, Alzheimer's disease, and vascular dementia). Study results were pooled with random effect meta-analyses.

RESULTS: We included 32 studies. The pooled hazard ratio for all-cause dementia was 1.36 [95% CI: 1.01, 1.83] following a clinical episode of HSV1/2, and 1.12 [95% CI: 1.00, 1.25] following a clinical episode of VZV. The pooled estimate for all-cause dementia following antiviral treatment and VZV was 0.88 [95% CI: 0.81, 0.96].

CONCLUSIONS: The present review of the scientific literature generally shows little evidence of an association between herpesviruses and risk of dementia. However, the review shows evidence of an association between antiviral treatment and a decreased risk of dementia. Because of considerable heterogeneity, future investigations could advantageously target certain subgroups.},
}

Humans
*Antiviral Agents/therapeutic use
*Dementia/epidemiology/virology
*Herpesviridae Infections/drug therapy/complications/epidemiology
*Herpesviridae
Risk Factors

@article {pmid40896959,
year = {2025},
author = {Yun, J and Moon, M and Yang, J and Yeom, HD and Lee, MH and Lee, G and Lee, JH},
title = {Molecular regulation and subtype-specific effects of naringenin and naringin on nicotinic acetylcholine receptors expressed in Xenopus oocytes.},
journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie},
volume = {191},
number = {},
pages = {118494},
doi = {10.1016/j.biopha.2025.118494},
pmid = {40896959},
issn = {1950-6007},
abstract = {Naringenin and naringin, bioactive flavonoids from citrus fruits, exhibit neuroprotective effects, showing promise for neurodegenerative diseases like Alzheimer's and Parkinson's. Additionally, they demonstrate significant anticancer potential, modulating key signaling pathways involved in tumor growth, apoptosis, and metastasis, thus expanding their therapeutic applications in cancer treatment. These compounds interact with nicotinic acetylcholine receptors (nAChRs), a class of ligand-gated ion channels critical for modulating neurotransmission within the central nervous system. In this study, naringenin and naringin were found to selectively inhibit specific subtypes of nAChRs in a concentration-dependent, reversible, and noncompetitive manner. These effects were examined using two-electrode voltage-clamp recordings in Xenopus laevis oocytes heterologously expressing various human nAChR subtypes, and further analyzed by site-directed mutagenesis and molecular docking simulations to identify key binding residues. Mutational analyses, supported by molecular docking, revealed that certain mutations in nAChRs eliminate naringin's inhibitory effect, highlighting a selective binding affinity. This inhibition was observed selectively in α3β2 and α3β4 nAChR subtypes, which are significant within the autonomic nervous system, while α7 and α4β2 nAChRs, often implicated in neurodegenerative processes, remained unaffected. These findings suggest that naringenin and naringin could be developed as targeted modulators of nAChRs, offering therapeutic potential.},
}

@article {pmid40896796,
year = {2025},
author = {Dirir, AM and Ali, A and Hachem, M},
title = {Recent Advancements in Lipid Nanoparticles-Based Phytoactives Delivery Systems for Neurodegenerative Diseases.},
journal = {International journal of nanomedicine},
volume = {20},
number = {},
pages = {10279-10300},
doi = {10.2147/IJN.S537566},
pmid = {40896796},
issn = {1178-2013},
abstract = {Neurodegenerative diseases, including Alzheimer's and Parkinson's diseases, pose a significant and continuous burden on the healthcare system, urging the search for innovative therapeutical approaches targeting the central nervous system. Nowadays, no definitive treatment can effectively modulate the neuronal degeneration associated with such diseases. The current line of therapies is primarily symptomatic and suffers several drawbacks. Among these, phytochemicals are emerging for their potential in the management of neurodegenerative disorders. Indeed, plants produce secondary metabolites that provide defensive functions against abiotic and biotic stresses. These metabolites can target the neurons and represent a promising therapeutic intervention for neurological disorders. However, the polar nature of phytochemicals and their large size hinder their passage through the blood-brain barrier, a selective barrier separating blood and the brain. Emerging studies have shown that the therapeutic efficiency of phytochemicals has been enhanced following their encapsulation with engineered nanocarriers such as lipid nanoparticles. Recent research indicates that delivering phytochemicals through lipid nanoparticles improves their physiological stability, promotes their passage across the blood-brain barrier, and enhances their accumulation in brain tissue-resulting in more effective neuroprotective effects than their free, unencapsulated form. Hence, the aim of the present review is to highlight the application of lipid nanoparticles as carriers for phytoactives with neuroprotective properties, discuss the current challenges associated with such nanocarriers, and provide insights into potential future research work.},
}

@article {pmid40896259,
year = {2025},
author = {Xu, J and Jin, H and Li, X and Jiang, Z and Meng, F and Wang, W and Li, WY},
title = {ADAM17 Inhibition Protects Cognition in Intermittent Hypoxia: The Role of TREM2.},
journal = {Nature and science of sleep},
volume = {17},
number = {},
pages = {1915-1928},
doi = {10.2147/NSS.S513304},
pmid = {40896259},
issn = {1179-1608},
abstract = {PURPOSE: The triggering receptor expressed on myeloid cells 2 (TREM2) is a new therapeutic target in Alzheimer's disease. However, its role in obstructive sleep apnea (OSA)-related cognitive impairment is still unclear. This study aimed to investigate the effect and regulatory mechanism of TREM2 on cognitive impairment related to OSA.

METHODS: Since intermittent hypoxia (IH) is the primary pathophysiologic characteristic of OSA, we conducted IH animal and BV2 cell model to investigate the mechanism. Trem2 knockdown and Trem2 overexpression cells were created by Lentivirus transfection. A disintegrin and metalloprotease 17 (ADAM17) is the primary enzyme for TREM2 shedding, we used TAPI-1 to inhibit its activity. Morris water maze, Nissl staining, real-time PCR, immunofluorescence, Western blotting, fluorometric assay kit, and enzyme-linked immunosorbent assay were used to explore the molecular mechanism.

RESULTS: The TREM2 levels were decreased in BV2 cells exposed to IH for 24 hours. IH elevated the levels of IL-1β, TNF-α and CD86 in BV2 cells, as well as the levels of p-Tau in conditioned media-cultured HT-22 cells. Conversely, IH reduced the levels of IL-10 and CD206 in BV2 cells. However, these effects were exacerbated in BV2 cells with Trem2 knockdown, whereas they were mitigated in those with Trem2 overexpression. Additionally, the ADAM17 activity and soluble TREM2 (sTREM2) levels were increased in BV2 cells subjected to IH. Treatment with TAPI-1, suppressed ADAM17 activity and restored TREM2 expression both in vitro and in vivo. Inhibition of ADAM17 led to a reduction in the expression of CD86, IL-1β, TNF-α and p-Tau levels, while enhancing the expression of CD206, IL10 and cognitive functions.

CONCLUSION: TREM2 played a protective role in IH-induced neuroinflammation and neuronal injury by promoting microglia M2 polarization. IH caused excessive activation of ADAM17 and resulted in augmented degradation of TREM2. Restoring TREM2 expression by inhibiting ADAM17 indicates a potentially promising therapeutic strategy for cognitive impairment in OSA.},
}

@article {pmid40895811,
year = {2025},
author = {Tysinger, B and Wei, Y and Heun-Johnson, H and Zissimopoulos, JM},
title = {Long-term value of lecanemab to individuals and families.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {11},
number = {3},
pages = {e70151},
doi = {10.1002/trc2.70151},
pmid = {40895811},
issn = {2352-8737},
abstract = {INTRODUCTION: An assessment of the value of lecanemab for patients living with Alzheimer's disease (AD) and their care partners provides them and their health-care providers important information for deciding treatment initiation.

METHODS: We used data from a nationally representative sample of middle aged and older Americans combined with data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) on AD progression and data on lecanemab treatment effects from Clarity AD clinical trials. We use dynamic microsimulation modeling to quantify the long-term health and economic value of lecanemab for persons living with AD and their care partners.

RESULTS: We quantified five measures of value: quality of life of the persons living with AD and their care partners, medical costs, caregiving costs, and earnings, and estimated that lecanemab had a value of $21,398 relative to no treatment after 4 years and $37,943 after 10 years. Extending the treatment to 48 months resulted in a value of $42,821 relative to no treatment after 4 years and $95,311 after 10 years. Forty-eight months of a similar next-generation therapy but with 50% efficacy in slowing cognitive and functional decline resulted in a value of $82,116 relative to no treatment after 4 years and $189,691 after 10 years.

DISCUSSION: Over time, lecanemab treatment reduced medical costs, hours of care required from care partners, and improved quality of life. There is much value to be gained with next-generation treatments that have a larger impact on slowing decline. Considering a wider range of outcomes in future assessments will provide a more complete understanding of value to support decision making about treatment initiation and about reimbursement for payers.

HIGHLIGHTS: There is significant value of lecanemab for persons with mild cognitive impairment or mild dementia.Over time, lecanemab reduces medical costs, caregiver hours, and improves the quality of life of persons living with Alzheimer's disease (AD) and their care partners.A next-generation treatment for AD with similar features to lecanemab but higher efficacy, more than doubles the value.Assessing therapy value supports decision making by patients and their health-care providers.},
}

@article {pmid40895150,
year = {2025},
author = {Chen, G and Su, Y and Chen, S and Lin, T and Lin, X},
title = {Polyphenols and Alzheimer's Disease: A Review on Molecular and Therapeutic Insights With In Silico Support.},
journal = {Food science & nutrition},
volume = {13},
number = {9},
pages = {e70496},
doi = {10.1002/fsn3.70496},
pmid = {40895150},
issn = {2048-7177},
abstract = {Alzheimer's disease (AD), a progressive neurodegenerative disorder, characterized by amyloid-beta (Aβ) aggregation, tau hyperphosphorylation, oxidative stress, and neuroinflammation resulted the cognitive memory loss. Despite extensive research, effective therapeutic treatment remains elusive. Polyphenols, naturally occurring bioactive compounds, have emerged as promising neuroprotective agents due to their potent antioxidant, anti-inflammatory, and amyloid-modulating properties. Research indicated that these bioactive compounds have potent antioxidant and anti-inflammatory properties, have garnered significant attention for their potential role in combating AD by targeting its key pathological mechanisms. Preclinical studies highlight the efficacy of various polyphenols, such as resveratrol, curcumin, and epigallocatechin gallate, in improving cognitive function and reducing neurodegeneration. Moreover, in silico approaches, displayed polyphenols mechanistic interactions with key AD targets to reduce pathogenesis. These computational models accelerate drug discovery by predicting binding affinities, optimizing structural modifications, and identifying novel polyphenol derivatives with enhanced therapeutic potential. This review explores the multifaceted role of polyphenols in AD mitigation, emphasizing their impact on oxidative stress and neuroinflammation while integrating in silico evidence to reinforce their therapeutic relevance. Convincingly, through the suppression of key mediators of AD, including oxidative stress, neuroinflammation, amyloid-beta and tau proteins, polyphenols exhibited outstanding therapeutic potential to treat AD.},
}

@article {pmid40894925,
year = {2025},
author = {He, G and Huang, J and Zeng, Z and Sun, H and Wu, C and Xu, Q and Hu, C and Jin, B and Tong, M and Wang, C},
title = {Stem cell therapy offers new hope for the treatment of Alzheimer's disease.},
journal = {Frontiers in cell and developmental biology},
volume = {13},
number = {},
pages = {1650885},
doi = {10.3389/fcell.2025.1650885},
pmid = {40894925},
issn = {2296-634X},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder primarily characterized by memory impairment and cognitive decline, for which no curative treatment is currently available. Existing therapeutic strategies, such as cholinesterase inhibitors and N-methyl-D-aspartate (NMDA) receptor antagonists, can only provide limited symptomatic relief and fail to halt disease progression. In recent years, stem cell therapy has emerged as a promising approach for AD due to its multifaceted mechanisms of action. The therapeutic effects of stem cells in AD are mainly attributed to their ability to differentiate into functional neurons or glial cells, thereby replacing damaged cells and repairing neural networks. In addition, stem cells secrete neurotrophic and anti-inflammatory factors that contribute to the improvement of the brain microenvironment. Furthermore, they can regulate neuroinflammation, promote the clearance of β-amyloid (Aβ) deposits, and suppress neuroinflammation, thus potentially slowing disease progression. However, several challenges remain, including low cell survival rates, immune rejection, tumorigenic risks, and difficulties in crossing the blood-brain barrier. Looking ahead, the integration of advanced technologies such as organoid models, gene editing, artificial intelligence, and multi-omics approaches may drive substantial progress in the clinical translation of stem cell therapies for AD. Although still in its early stages, the future of this therapeutic strategy holds great promise.},
}

@article {pmid40894255,
year = {2025},
author = {Hu, N and Chen, L and Hu, G and Ma, R},
title = {Advancements in extracellular vesicle therapy for neurodegenerative diseases.},
journal = {Exploration of neuroprotective therapy},
volume = {5},
number = {},
pages = {},
doi = {10.37349/ent.2025.1004104},
pmid = {40894255},
issn = {2769-6510},
abstract = {Neurodegenerative diseases represent a significant and growing challenge to public health worldwide. Current therapeutic strategies often fall short in halting or reversing disease progression, highlighting the urgent need for novel approaches. Extracellular vesicles (EVs) have garnered attention as potential therapeutic agents due to their role in intercellular communication and their ability to transport bioactive cargo, including proteins, nucleic acids, and lipids. This review provides a comprehensive overview of the biology of EVs, their involvement in neurodegenerative diseases, and the potential for EV-based therapies. We discuss the different types of EVs, their biogenesis, and their cargo composition, emphasizing their relevance to neurological processes such as protein misfolding, neuroinflammation, and oxidative stress. Preclinical studies investigating EVs as carriers of therapeutic cargo and their ability to promote neuronal survival and regeneration are examined, with a focus on evidence from animal models of neurodegenerative disorders. We explore the use of EVs in the treatment of neurodegenerative diseases, including ongoing clinical trials, methods for EV isolation and modification, and future perspectives on personalized EV-based therapies designed to meet the unique needs of individual patients. Overall, this review highlights the potential of EVs as a promising avenue for neurodegenerative disease therapy, while also addressing key research gaps and translational hurdles that need to be overcome for their successful clinical implementation.},
}

@article {pmid40894003,
year = {2025},
author = {Kridawati, A and Indrawati, L and Hadisaputra, S and Adawiyah, AR},
title = {The preventive role of tempeh isoflavones on menopausal women's cognitive function: A multiple mechanism pathway.},
journal = {Journal of Alzheimer's disease reports},
volume = {9},
number = {},
pages = {25424823251371284},
doi = {10.1177/25424823251371284},
pmid = {40894003},
issn = {2542-4823},
abstract = {Cognitive dysfunction in the elderly is not only a disease but also could be considered a preclinical condition of Alzheimer's disease (AD), one of the most common types of dementia in the elderly. Therefore, treatment such as early detection and management of risk factors that could slow and prevent the onset of dementia is necessary for the elderly. Estrogen reduces the risk of AD in postmenopausal women. It has also been shown to reduce amyloid-β (Aβ) pathology in animal models of AD and suppress Aβ secretion from neuronal tissue. Estrogen receptors are involved in cognitive processes such as learning and memory, the formation of the hippocampus, the amygdala, and the cerebral cortex. Hormone replacement therapy (HRT) could improve cognition and thus delay the development of AD. Giving HRT after 9 years has been shown to increase the risk of breast cancer two-fold and cardiovascular disease. Phytoestrogens are hormones found in plants that can be an alternative to HRT. One of the foods that contains phytoestrogens and is widely consumed in Indonesia is tempeh. Isoflavone is a dominant phytoestrogen, structurally an estrogen-like substance, and functionally similar to 17β-estradiol. In this review article, we will discuss the role of tempeh isoflavones in a mechanism pathway on cognition.},
}

@article {pmid40893997,
year = {2025},
author = {Mokwenye, RC},
title = {A thematic analysis of Lay knowledge and beliefs about dementia among first-generation Black African immigrants from West Africa living in London: Informed by a grounded theory approach.},
journal = {Journal of public health research},
volume = {14},
number = {3},
pages = {22799036251368446},
doi = {10.1177/22799036251368446},
pmid = {40893997},
issn = {2279-9028},
abstract = {BACKGROUND: Many Black Africans live in the UK. More than 850,000 people live with dementia in the UK, and more than 25,000 people with dementia are from Black and minority ethnic groups. The study explores themes of lay knowledge and beliefs about dementia.

DESIGN AND METHODS: This study employs a qualitative research design and methods to explore lay knowledge and beliefs about dementia amongst Black African populations living in London. The research is philosophically underpinned by social constructionism and sociological and anthropological lay concepts of health and illness. The researcher interviewed 31 adult respondents, male and female, from the Black African community in London to generate rich data. Participants were first-generation immigrants from West Africa living in London and were mainly carers. Thematic data analysis informed by a grounded theory approach was used to analyse the data.

RESULTS: The findings show that dementia is a complex biopsychosocial phenomenon. Four key themes with subthemes emerged and were developed: (i) Traditional views, (ii) Disease and illness, (iii) Help-seeking, and (iv) Caregiving and treatment. The group's understanding of dementia evolved from traditional views to a more medical perspective. This study added witchcraft to the dementia literature on BAME in the UK.

CONCLUSIONS: The study concluded that the group does not lack knowledge of dementia. Their understanding and beliefs about dementia are evolving, and further efforts are needed to enhance awareness through education, training, and outreach to support individuals with dementia and their families within the Black African community.},
}

@article {pmid40893935,
year = {2025},
author = {Wu, H and Shi, J and Wang, X and Yang, M and Cai, J},
title = {A rare intronic c.2654+1G>A mutation in CSF1R-microglial encephalopathy: a case report.},
journal = {Frontiers in genetics},
volume = {16},
number = {},
pages = {1593964},
doi = {10.3389/fgene.2025.1593964},
pmid = {40893935},
issn = {1664-8021},
abstract = {OBJECTIVE: We report a case of CSF1R-microglial encephalopathy associated with a rare intronic c.2654 + 1G>A mutation, featuring negative diffusion-weighted imaging (DWI) findings and a cerebrospinal fluid (CSF) biomarker profile indicative of Alzheimer's disease-related changes, and we explore the associations between genetic mutations, CSF biomarker alterations, and neuroimaging manifestations.

METHODS: This study documents the demographic data, detailed medical history, and clinical manifestations of a patient with CSF1R-microglial encephalopathy. The medical histories of some family members were collected, and the proband underwent whole-exome sequencing (WES) for diagnostic confirmation.

RESULTS: The patient, a 53-year-old woman, presented with early-onset cognitive decline, personality changes, and behavioral abnormalities. Neuropsychological testing revealed severe cognitive impairment, and the CSF biomarker profile suggested Alzheimer's disease-related changes. Cranial MRI showed bilateral, symmetric deep white matter changes, brain atrophy (including corpus callosum thinning), and low signal intensity on DWI. Family history revealed that 3 out of 19 individuals across four generations, including the proband, her aunt, and her sister, developed dementia and progressed to severe cognitive impairment rapidly. WES analysis revealed a heterozygous c.2654 + 1G>A variant in the CSF1R gene (NM_005211.3), confirming a diagnosis of CSF1R-microglial encephalopathy caused by a dominant autosomal mutation in exon 20 of the CSF1R gene.

CONCLUSION: CSF1R-microglial encephalopathy is a progressive disorder with diverse early clinical presentations, making it prone to misdiagnosis and delayed treatment. This case suggests that, contrary to previous findings, negative DWI results should not exclude CSF1R-microglial encephalopathy. In addition, CSF biomarker profiles in patients with CSF1R-microglial encephalopathy may exhibit Alzheimer's disease-related changes. Early genetic testing is critical, and for genetically linked diseases, testing other family members can help ensure early diagnosis and intervention.},
}

@article {pmid40893870,
year = {2025},
author = {Kwak, MG and Mao, L and Zheng, Z and Su, Y and Lure, F and Li, J},
title = {A Cross-Modal Mutual Knowledge Distillation Framework for Alzheimer's Disease Diagnosis: Addressing Incomplete Modalities.},
journal = {IEEE transactions on automation science and engineering : a publication of the IEEE Robotics and Automation Society},
volume = {22},
number = {},
pages = {14218-14233},
doi = {10.1109/tase.2025.3556290},
pmid = {40893870},
issn = {1545-5955},
abstract = {Early detection of Alzheimer's Disease (AD) is crucial for timely interventions and optimizing treatment outcomes. Integrating multimodal neuroimaging datasets can enhance the early detection of AD. However, models must address the challenge of incomplete modalities, a common issue in real-world scenarios, as not all patients have access to all modalities due to practical constraints such as cost and availability. We propose a deep learning framework employing Incomplete Cross-modal Mutual Knowledge Distillation (IC-MKD) to model different sub-cohorts of patients based on their available modalities. In IC-MKD, the multimodal model (e.g., MRI and PET) serves as a teacher, while the single-modality model (e.g., MRI only) is the student. Our IC-MKD framework features three components: a Modality-Disentangling Teacher (MDT) model designed through information disentanglement, a student model that learns from classification errors and MDT's knowledge, and the teacher model enhanced via distilling the student's single-modal feature extraction capabilities. Moreover, we show the effectiveness of the proposed method through theoretical analysis and validate its performance with simulation studies. In addition, our method is demonstrated through a case study with Alzheimer's Disease Neuroimaging Initiative (ADNI) datasets, underscoring the potential of artificial intelligence in addressing incomplete multimodal neuroimaging datasets and advancing early AD detection.},
}

@article {pmid40893127,
year = {2025},
author = {Lai, Z and Ke, L and Zhao, W},
title = {Naringenin as a neurotherapeutic agent in Alzheimer's disease: epigenetic signatures, gut microbiota alterations, and molecular neuroprotection.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1647967},
doi = {10.3389/fnagi.2025.1647967},
pmid = {40893127},
issn = {1663-4365},
abstract = {Alzheimer's disease (AD) remains a major neurodegenerative disorder characterized by progressive cognitive decline, amyloid-β (Aβ) aggregation, tau pathology, oxidative stress, and chronic neuroinflammation. In recent years, the dietary flavonoid naringenin, abundant in citrus fruits, has gained attention as a multi-target neuroprotective agent with potential application in AD therapy. Preclinical studies demonstrate that naringenin exhibits robust antioxidant activity, notably through activation of the nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response element (ARE) signaling pathway, which reduces ROS and preserves mitochondrial integrity. Furthermore, naringenin upregulates AMPK-mediated autophagy, aiding in the clearance of toxic Aβ peptides and promoting neuronal survival. Inflammatory cascades are significantly downregulated following naringenin treatment. Additionally, naringenin modulates estrogen receptor and PI3K/Akt signaling, contributing to enhanced neuronal viability and reduced apoptosis. Notably, its ability to inhibit acetylcholinesterase suggests promise for restoring cholinergic neurotransmission. Despite these benefits, naringenin's poor solubility and limited oral bioavailability hinder clinical translation. To address these challenges, advanced nanocarrier-based delivery systems have been engineered to facilitate blood-brain barrier penetration and sustained brain targeting, markedly improving cognitive outcomes in animal models. Safety profiles in rodents indicate low toxicity at therapeutic doses, reinforcing its viability as a candidate compound. This review highlights the multifaceted mechanisms and delivery strategies of naringenin in AD, and underscores the need for well-designed clinical trials to confirm its efficacy and safety in humans.},
}

@article {pmid40893125,
year = {2025},
author = {Gu, Z and Ge, B and Wang, Y and Gong, Y and Qi, M},
title = {Artificial intelligence technologies for enhancing neurofunctionalities: a comprehensive review with applications in Alzheimer's disease research.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1609063},
doi = {10.3389/fnagi.2025.1609063},
pmid = {40893125},
issn = {1663-4365},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative condition that impairs memory and cognition, presenting a growing global healthcare burden. Despite major research efforts, no cure exists, and treatments remain focused on symptom relief. This narrative review highlights recent advancements in artificial intelligence (AI), particularly machine learning (ML) and deep learning (DL), which enhance early diagnosis, predict disease progression, and support personalized treatment strategies. AI applications are reshaping healthcare by enabling early detection, predicting disease progression, and developing personalized treatment plans. In particular, AI's ability to analyze complex datasets, including genetic and imaging data, has shown promise in identifying early biomarkers of AD. Additionally, AI-driven cognitive training and rehabilitation programs are emerging as effective tools to improve cognitive function and slow down the progression of cognitive impairment. The paper also discusses the potential of AI in drug discovery and clinical trial optimization, offering new avenues for the development of AD treatments. The paper emphasizes the need for ongoing interdisciplinary collaboration and regulatory oversight to harness AI's full potential in transforming AD care and improving patient outcomes.},
}

@article {pmid40893124,
year = {2025},
author = {Kayano, M},
title = {Exploring efficient and effective mammalian models for Alzheimer's disease.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1652754},
doi = {10.3389/fnagi.2025.1652754},
pmid = {40893124},
issn = {1663-4365},
abstract = {The aim of this study was to explore and discuss efficient and effective mammalian models for Alzheimer's disease (AD). In this study, efficient AD models are characterized by a small body size, a short lifespan, and rapid development of the main pathology including amyloid plaque formation. Effective AD models are expected to exhibit not only the main pathology, but also co-pathology associated with other neurodegenerative diseases (e.g., Lewy body dementia), systemic disturbances such as disrupted central-peripheral homeostasis, and sleep-circadian failures. This reflects recent findings indicating that AD is far more multifactorial than previously assumed. Although further investigation is required, non-human primates, particularly common marmosets (Callithrix jacchus), and dogs (Canis lupus familiaris) are candidates of promising and effective AD models. Tree shrews (Tupaia belangeri), guinea pigs (Cavia porcellus), and evolutionary related species including degus (Octodon degus) constitute an alternative group of AD models that remain underexplored but potentially efficient and effective. These mammalian models, together with hypothesis-driven mouse models and advances in data science technologies including omics and imaging analyses, may lead to breakthroughs in AD research, resulting in the development of effective prevention and treatment for AD.},
}

@article {pmid40891144,
year = {2025},
author = {Pascali, V and Tosoni, D and Altieri, S and Protti, N},
title = {Capture-enhanced neutron irradiation to treat Alzheimer's disease: Design of a small animal set-up for future in-vivo experiments.},
journal = {Medical physics},
volume = {52},
number = {9},
pages = {e18062},
doi = {10.1002/mp.18062},
pmid = {40891144},
issn = {2473-4209},
support = {964934//European Commission/ ; },
mesh = {*Alzheimer Disease/radiotherapy ; Animals ; Mice ; Monte Carlo Method ; *Boron Neutron Capture Therapy/instrumentation/methods ; *Neutrons/therapeutic use ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is characterized by the accumulation of β $\beta$ -Amyloid and τ $\tau$ proteins in the brain that causes dementia. To date, there is no cure capable of eradicating AD, so it is necessary to study a performing therapy. The NECTAR project aims to investigate an extension of the conventional Boron Neutron Capture Therapy principles as a possible treatment for AD at different scales (protein, cells, animal).

PURPOSE: The present study focuses on a macroscopic scale and wants to propose an irradiation set-up for mice in the thermal column (TC) of the Triga Mark II reactor of Pavia University, in view of the forthcoming in vivo irradiation of healthy and transgenic AD mouse models.

METHODS: Monte Carlo simulations were carried out with the MCNP6 code to test different irradiation positions and study the least toxic treatment possible by modeling neutron shielding to preserve healthy tissue. A shielding prototype was built and tested by means of neutron activation measurements. A geometrical mouse model was developed with the aim of computing the dose-rates induced in each radiosensitive organ and thus to estimate possible irradiation times for future in vivo experiments.

RESULTS: The computational study showed that the safest irradiation condition involves placing the shielding 20 cm from the TC entrance and that the best performing shielding material is 6 Li $^{6}{
\rm Li}$
enriched lithium carbonate. Furthermore, taking into account the tolerance doses of each organ, the maximum animal irradiation time in an AD context is 45 min. The proposed set-up could also be used for preclinical studies on brain tumors; in this context, the maximum estimated irradiation time is 11 min.

CONCLUSION: The proposed work is pivotal in the study of a possible treatment for AD in a neutron irradiation context, paving the way for the next phase of the NECTAR project involving in vivo irradiation of AD mouse models and thus making it possible to assess its efficacy and its possible future extension to the human brain.},
}

*Alzheimer Disease/radiotherapy
Animals
Mice
Monte Carlo Method
*Boron Neutron Capture Therapy/instrumentation/methods
*Neutrons/therapeutic use

@article {pmid40891036,
year = {2025},
author = {Wang, B and Wang, ZX and Lv, LM and Wang, X and Lu, JC and Zhao, YF and Jiang, R and Li, QF and Kong, Y and Yang, XW and Luo, J and Xiao, ZC and Li, AP and Yang, G and Ma, QH and Shao, L},
title = {Tenascin-R aggravates Aβ production in the perforant pathway by regulating Nav1.6 activity in APP/PS1 mice.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {9},
pages = {e70633},
doi = {10.1002/alz.70633},
pmid = {40891036},
issn = {1552-5279},
support = {82471464 to L.S.//National Natural Science Foundation of China/ ; 82301700 to B.W.//National Natural Science Foundation of China/ ; 82503370 to G.Y.//National Natural Science Foundation of China/ ; 2024-MS-157 to B.W.//Liaoning Province Natural Science Foundation/ ; ZR2023QH126 to X.W.//Shandong Provincial Natural Science Foundation/ ; LJ222510161002 to L.S.//Leading Talents Team Project of Liaoning Provincial Department of Education/ ; },
mesh = {Animals ; *NAV1.6 Voltage-Gated Sodium Channel/metabolism ; Mice ; *Amyloid beta-Peptides/metabolism ; Mice, Transgenic ; *Tenascin/metabolism/genetics ; Amyloid beta-Protein Precursor/genetics/metabolism ; *Alzheimer Disease/metabolism/genetics ; Disease Models, Animal ; Hippocampus/metabolism ; },
abstract = {INTRODUCTION: Alzheimer's disease (AD) neuropathology exhibits early accumulation of amyloid beta (Aβ) plaques within the perforant pathway. This study explores how tenascin-R, a myelin-associated protein at nodes of Ranvier (NORs), modulates Aβ generation through Nav1.6 within this cortico-hippocampal circuit.

METHODS: We integrated genetic, electrophysiological, and microdialysis techniques in APP/PS1 mice and constructed tenascin-R gene fragments and GEDC motif to identify potential therapeutic sequences for AD treatment.

RESULTS: Stimulating the entorhinal cortex increased Aβ1-42 release along the perforant pathway through Nav-dependent mechanisms. Reducing tenascin-R decreased Aβ deposition and alleviated cognitive deficits. Overexpressing tenascin-R enhanced Nav1.6 currents and upregulated amyloid precursor protein and β-secretase. The GEDC motif within tenascin-R's epidermal growth factor-like domain controlled Nav1.6 activity.

DISCUSSION: Our findings demonstrate that NORs signaling modulates Aβ processing independently of synaptic mechanisms. Tenascin-R regulates Aβ pathogenesis via Nav1.6 at NORs, underscoring myelin proteins and Nav1.6 as therapeutic targets. The GEDC motif represents a potential peptide-based compound for AD therapy.

HIGHLIGHTS: Nodes of Ranvier-associated tenascin-R (Tn-R) regulate amyloid beta (Aβ) production in the perforant pathway of APP/PS1 mice. Tn-R enhances Nav1.6-mediated sodium currents, promoting amyloid precursor protein (APP) transcription and Aβ generation. Genetic downregulation of Tn-R mitigates Aβ deposition, restores synaptic integrity, and improves cognition. The conserved GEDC motif within Tn-R's epidermal growth factor-like domain is critical for modulating Nav1.6 activity and amyloidogenesis. The Tn-R/Nav1.6 axis represents a novel therapeutic target for Alzheimer's disease, with GEDC-derived peptides offering translational potential.},
}

Animals
*NAV1.6 Voltage-Gated Sodium Channel/metabolism
Mice
*Amyloid beta-Peptides/metabolism
Mice, Transgenic
*Tenascin/metabolism/genetics
Amyloid beta-Protein Precursor/genetics/metabolism
*Alzheimer Disease/metabolism/genetics
Disease Models, Animal
Hippocampus/metabolism

@article {pmid40890909,
year = {2025},
author = {Maheta, P and Patel, C and Parmar, D and Beladiya, J and Patel, S and Sheth, D and Dholakia, S},
title = {Neuroprotective Effects of a 3-Amino Quinazoline Derivative via Keap1-Nrf2 Pathway Activation in an ICV-STZ-Induced Rat Model of Sporadic Alzheimer's Disease.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.5c00540},
pmid = {40890909},
issn = {1948-7193},
abstract = {The Keap1-Nrf2 pathway has emerged as a promising target for Alzheimer's disease (AD). This study employed in silico modeling to identify Nrf2 activators through Keap1 inhibition. The most promising quinazoline derivative, LMDP10, was then evaluated in a rat model of sporadic AD induced by Intracerebroventricular (ICV) streptozotocin (STZ). ICV STZ-induced rats were treated with LMDP10 (5-50 mg/kg, orally). Behavioral changes were assessed using the Morris water maze (MWM) and novel object recognition (NOR) tests. Additionally, neurochemical marker (oxidant/antioxidant), proinflammatory cytokine (TNF-α) levels, Nrf2 levels, and histopathological alterations were analyzed in both the hippocampus and cortex. An oral toxicity study of LMDP10 was performed according to the OECD Guideline 425. LMDP10 treatment (50 mg/kg/day) significantly improved memory performance (increased percentage time spent in target quadrant in the MWM test and increased discrimination index in the NOR test; P < 0.001 for both). Notably, this dose also significantly increased Nrf2, SOD, and GSH levels while attenuating elevated MDA and TNF-α levels in both brain regions compared to those in vehicle-treated STZ rats. LMDP10 emerged as a potential therapeutic candidate for AD. LMDP10 improved memory function and increased Nrf2 signaling and antioxidant defenses while reducing neuroinflammation. These findings suggest that the neuroprotective effects of LMDP10 may involve Keap1-Nrf2 pathway activation, warranting further investigation of its therapeutic potential in AD.},
}

@article {pmid40890872,
year = {2025},
author = {Yuan, M and Nguyen, TTT and Gibb, AJ and Xian, YF and Xu, HX},
title = {Potential of phytochemicals in the treatment of Alzheimer disease by modulating lysosomal dysfunction: a systematic review.},
journal = {Chinese medicine},
volume = {20},
number = {1},
pages = {138},
pmid = {40890872},
issn = {1749-8546},
support = {82204723//National Natural Science Foundation of China/ ; },
abstract = {Alzheimer disease (AD) is a primary international health dilemma, especially in elderly populations, due to its progressive nature and its adverse cognitive impact. The dysfunction of lysosomes, which impairs protein degradation and leads to toxic accumulation in neurons, is a pivotal factor in AD. We explore phytochemicals that specifically target lysosomal dysfunction via the activation of autophagy, phagocytosis, and lysosome function, exhibiting anti-inflammatory and antioxidant properties. This study involves extracting and evaluating phytochemicals by exploring multiple databases, Google Scholar, PubMed, the Science Citation Index Expanded (SCIE), and the China National Knowledge Infrastructure (CNKI), integrating contemporary biochemical evidence with TCM principles-highlighting the interconnected roles of deficiency, stasis, and phlegm-to provide a comprehensive therapeutic framework. Key phytochemicals-magnolol, trehalose, and salidroside- demonstrate notable promise in enhancing lysosomal function, reducing amyloid beta accumulation, and improving cognitive outcomes. Addressing traditional theory and modern science, we underline the potential for future research by clarifying the mechanisms of compounds and their effectiveness, which may delay the disease process.},
}

@article {pmid40889776,
year = {2025},
author = {Cemali, SH and Poyraz, S and Belveren, S and Taş, S and Tamer, MA and Döndaş, NY and Döndaş, HA and Sansano, JM},
title = {Recent Insights in Multi-Target Drugs in Pharmacology and Medicinal Chemistry.},
journal = {ChemMedChem},
volume = {},
number = {},
pages = {e202500447},
doi = {10.1002/cmdc.202500447},
pmid = {40889776},
issn = {1860-7187},
support = {TSA-2022-15050//Çukurova University/ ; TSA-2021-13814//Çukurova University/ ; FYL-2023-15939//Çukurova University/ ; TSA-2023-16116//Çukurova University/ ; TYL-2024-17047//Çukurova University/ ; },
abstract = {Many of the drugs used in treatment today have been designed based on the "specificity paradigm". Resistance has developed against drugs designed using this approach, leading to a decrease in their effectiveness. In addition, it is well-documented in the literature that diseases with complex etiologies, such as Alzheimer's, Parkinson's, and cancer are influenced by multiple genetic and/or environmental factors. As a result, specificity paradigm is often insufficient for treating these diseases. Therefore, there is a need to develop drugs that interact with multiple targets simultaneously through different mechanisms. This review aims to provide an overview of the methods used in multitarget drug design, the reactions employed in the synthesis of these drugs, their applications, and recent research conducted in this field.},
}

@article {pmid40889628,
year = {2025},
author = {Çam Özünlü, SA and Uysal, F and Doğan, HT and Parlar, A and Çetinkaya, A and Arslan, SO},
title = {Thymoquinone ameliorates cognitive impairment and neuroinflammation in an amyloid-beta-induced rat model of Alzheimer's disease.},
journal = {Brain research},
volume = {},
number = {},
pages = {149918},
doi = {10.1016/j.brainres.2025.149918},
pmid = {40889628},
issn = {1872-6240},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and memory impairment. Amyloid-beta (Aβ) peptide accumulation is one of the most important chatacteristics of AD that cause neuronal damage and neuroinflammation. Thymoquinone (TQ), a bioactive compound derived from Nigella sativa, has shown neuroprotective properties in previous studies. This study aimed to evaluate the ameliorative effects of TQ in an Aβ1-42-induced AD rat model. Male Wistar-Albino rats were divided into four groups: Control, AD, TQ-10 (10 mg/kg TQ), and TQ-30 (30 mg/kg TQ). TQ was administered orally for 7 days before and 10 days after Aβ1-42 injection into the hippocampus. Cognitive functions were assessed using the Passive Avoidance (PA) and Morris Water Maze (MWM) tests. After behavioral experiments, hippocampal cytokine (tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β)) levels, as well as astrocyte and microglial activation, are evaluated. TQ treatment reversed memory impairements in the AD group. Hippocampal TNF-α and IL-1β levels were elevated in the AD and reduced in TQ-treated groups. Immunohistochemical analysis revealed that the increased reactivity of glial fibrillary acidic protein (GFAP) and ionized calcium-binding adapter molecule 1 (Iba1) in the AD group was significantly attenuated by TQ treatment. Both 10 mg/kg and 30 mg/kg doses of TQ administration improved cognitive performance, reduced neuroinflammation, and mitigated glial activation in an Aβ-induced AD rat model. These findings suggest that TQ may serve as a promising neuroprotective agent for AD. Further studies are required to elucidate its molecular mechanisms and therapeutic potential in clinical settings.},
}

@article {pmid40889010,
year = {2025},
author = {Gote, S and Dubey, S and Nargund, SL and Thapa, S},
title = {A systematic review of natural products targeting Nrf2-Keap1-ARE pathway and their influence on neurodegenerative disorders.},
journal = {Inflammopharmacology},
volume = {},
number = {},
pages = {},
doi = {10.1007/s10787-025-01917-5},
pmid = {40889010},
issn = {1568-5608},
abstract = {Neurodegenerative disease represents a significant public health concern, with conditions, such as Alzheimer's disease and Parkinson's disease, being among the most prevalent. The primary risk factor for these neurodegenerative diseases is the process of aging. Key factors, such as oxidative stress and mitochondrial dysfunction, play a crucial role in initiating neurodegeneration. The progressive deterioration and neuronal loss in both the central and peripheral nervous systems are hallmark features of neurodegenerative diseases. Plant-derived natural products and their bioactive components, such as curcumin, resveratrol, genistein, marine algae, quercetin, apigenin, and luteolin, have shown promise as therapeutic agents for treating neurodegenerative diseases. There are various medications approved for the management of neurodegenerative diseases; their usage is primarily limited to providing symptomatic relief. The utilization of natural products holds significant promise for the prevention and treatment of neurodegenerative diseases (ND). The review provides evidence that natural products and their bioactive compounds could be beneficial in the treatment of neurodegenerative disorders. This article delineates the Keap1-Nrf2-ARE pathway's role in ND progression, shedding light on the therapeutic efficacy of natural products and their bioactive constituents that have demonstrated neuroprotective properties.},
}

@article {pmid40888949,
year = {2025},
author = {Tang, L and Liu, F and Sun, X and Yang, J and Liu, Y and Pan, X and Hao, L and Lou, F and Su, J},
title = {The Janus face of CaMKII: from memory consolidation to neurotoxic switch in Alzheimer's disease.},
journal = {Archives of toxicology},
volume = {},
number = {},
pages = {},
pmid = {40888949},
issn = {1432-0738},
support = {32271160//Natural Science Foundation of China/ ; 2021M693914//China Postdoctoral Science Foundation/ ; 2022JH2/20200069//Scientific Research Project of Liaoning Province/ ; xtcx2019-11//Medical Electrophysiological Key Lab Foundation of Sichuan Province/ ; KeyME-2019-07//Key Laboratory Foundation of Medical Electrophysiology of Ministry of Education/ ; },
abstract = {Alzheimer's disease (AD), a neurodegenerative "memory killer" demanding urgent global intervention, has long been shrouded in mystery regarding its core pathological mechanisms. Although the traditional amyloid-β (Aβ) hypothesis remains dominant, recent groundbreaking research has revealed that early activation of aberrant calcium (Ca[2][+]) signaling pathways serves as the "initiating trigger" of AD pathogenesis-preceding even the formation of classical Aβ plaques-a discovery that fundamentally overturns the existing cognitive framework. This study systematically deconstructs, for the first time, the cascading regulatory network of the Ca[2][+]/CaM-CaMKII signaling axis in AD pathology, elucidating its potential links with core AD mechanisms, including the Aβ hypothesis, tau hyperphosphorylation, Ca[2][+] dyshomeostasis, synaptic dysfunction, and neuronal loss. Furthermore, this pathway not only triggers neurotoxic cascades through spatiotemporally specific regulation of synaptic Ca[2][+] overload but also directly disrupts neuroplasticity-the physical basis of memory encoding-by reshaping the dynamic equilibrium between long-term potentiation (LTP) and long-term depression (LTD).Crucially, the research uncovers the dual role of CaMKII as a "molecular switch": while physiologically maintaining memory consolidation via Thr286 autophosphorylation, its pathological overactivation due to Ca[2][+] dyshomeostasis leads to a "memory solidification-toxicity cycle." These findings establish a theoretical foundation for developing innovative therapies based on precise calcium signaling modulation-including Ca[2][+] homeostasis intervention and CaMKII allosteric modulators-offering a potential breakthrough in overcoming the long-standing limitation of "symptom relief without targeting root causes" in AD treatment.},
}

@article {pmid40888418,
year = {2025},
author = {Tansir, G and Rastogi, S and Gounder, MM},
title = {Repurposing nirogacestat, a gamma secretase enzyme inhibitor in desmoid tumors.},
journal = {Future oncology (London, England)},
volume = {},
number = {},
pages = {1-9},
doi = {10.1080/14796694.2025.2550826},
pmid = {40888418},
issn = {1744-8301},
abstract = {The gamma secretase (GS) enzyme controls cell-cell adhesion, neural stem cell proliferation, neo-angiogenesis, spinal maturation, and metabolism of amyloid precursor proteins (APP). Pathological production of abnormal amyloid-beta isoforms and senile plaques serves as the basis for pathogenesis of Alzheimer's disease (AD). GS enzyme inhibitors such as semagacestat and avagacestat were explored in AD but the studies were paused because of adverse events attributed to their influence on the Notch pathway.Crosstalk between Notch and Wnt signaling pathways created a potential role for GS inhibitors in the treatment of malignancies such as glioblastoma multiforme, pancreatic, and breast cancers. In a phase I study on nirogacestat among refractory solid malignancies, overall response rate (ORR) of 71.4% was observed in desmoid tumor (DT). The pivotal DeFi phase III trial established superiority of nirogacestat in terms of progression-free survival and ORR, reducing the likelihood of progression by 71%. Emphasis was placed on patient-reported outcomes (PRO) including the DT-specific tool, GOunder/Desmoid Tumor Research Foundation DEsmoid Symptom Scale (GODDESS).Nirogacestat received Food and Drug Administration (FDA) approval in November 2023 for management of progressive, unresectable, recurrent, or refractory DT. Further studies are underway to investigate other GS inhibitors such as AL-102 in the management of DT.},
}

@article {pmid40887393,
year = {2025},
author = {Hsu, JL and Park, KH and Panegyres, PK and Huang, YH and Eom, YI and Prusty, V and Tan, LS and Shea, YF},
title = {Early Alzheimer's disease (mild cognitive impairment or mild dementia): Prevalence, diagnostics, treatment options, and guidelines in Asia, Australasia, and Pacific nations countries.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {},
number = {},
pages = {100362},
doi = {10.1016/j.tjpad.2025.100362},
pmid = {40887393},
issn = {2426-0266},
abstract = {Early diagnosis of mild cognitive impairment (MCI) and Alzheimer's disease (AD) with mild dementia is becoming increasingly important to enable patients to receive appropriate treatment with available amyloid-targeting therapies. Reviews of AD prevalence and diagnostic and treatment patterns typically focus on global or western populations, but the situation in Asia, Australasia, and Pacific Nations (AAPN) countries is less clear. We performed a narrative review of literature for AD in several AAPN countries, focusing on patients with MCI or mild dementia who may benefit from early treatment. Published information regarding AD incidence and prevalence and current practice in AAPN countries is limited and the nature of available information differs between countries. However, AAPN countries include some of the most rapidly aging populations and show the associated increasing trend of all-cause dementia prevalence observed globally. Although lecanemab and donanemab are now approved for AD with MCI and mild dementia in several AAPN countries, the most appropriate diagnostic pathway for patients with MCI and early AD is not established. Even though the AAPN region includes countries with routine access to advanced technologies, concerns have already been raised about the ability of healthcare systems in Australia, New Zealand, and Korea to respond to approvals of new AD therapies, including the need to ensure availability of biomarker testing and dementia specialists to allow patients to receive the early diagnosis required to enable appropriate treatment. Guidelines and national policies also need updating to differentiate between dementia subtypes and include amyloid-targeting therapies for eligible patients with early AD.},
}

@article {pmid40887244,
year = {2025},
author = {Yamashita, C},
title = {[Development of Drug Delivery Systems Based on New Concepts].},
journal = {Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan},
volume = {145},
number = {9},
pages = {747-763},
doi = {10.1248/yakushi.25-00023},
pmid = {40887244},
issn = {1347-5231},
mesh = {*Drug Delivery Systems/trends ; Humans ; Alzheimer Disease/drug therapy ; Nanoparticles ; Pulmonary Disease, Chronic Obstructive/drug therapy ; Administration, Inhalation ; Animals ; *Drug Development/trends ; Lipids ; Liposomes ; },
abstract = {This review is a partial summary of the author's 40 years of research and development at Otsuka Pharmaceutical Co., Ltd. and the Faculty of Pharmaceutical Sciences, Tokyo University of Science. The author has consistently addressed issues of clinical significance and developed drug delivery systems based on new concepts through a change in thinking, free from preconceptions and stereotypes. In this review, the following research and development projects that the author has been involved in are described: a new concept inhalation system applicable to proteins and created based on a patient's perspective; a radical treatment for chronic obstructive pulmonary disease using a nuclear transfer strategy combining lipid nanoparticles and nuclear transfer signals for alveolar regeneration; a glycosylated Nose-to-Brain system for the development of innovative therapeutic agents for Alzheimer's disease.},
}

*Drug Delivery Systems/trends
Humans
Alzheimer Disease/drug therapy
Nanoparticles
Pulmonary Disease, Chronic Obstructive/drug therapy
Administration, Inhalation
Animals
*Drug Development/trends
Lipids
Liposomes

@article {pmid40887228,
year = {2025},
author = {Kawaguchi, Y and Takei, K},
title = {[Aβ Receptor PirB and its regulation by LOTUS].},
journal = {Nihon yakurigaku zasshi. Folia pharmacologica Japonica},
volume = {160},
number = {5},
pages = {318-323},
doi = {10.1254/fpj.25018},
pmid = {40887228},
issn = {0015-5691},
mesh = {Humans ; Animals ; *Alzheimer Disease/drug therapy/metabolism ; Amyloid beta-Peptides/metabolism ; Neuronal Plasticity ; *Receptors, Immunologic/metabolism/physiology ; },
abstract = {Over the years, research has accumulated a vast amount of knowledge about the pathogenesis of dementia, including Alzheimer's disease (AD). However, fundamental treatments for AD have not yet been established. In this article, we discuss an Aβ receptor, paired immunoglobulin like receptor B (PirB) and its endogenous regulator lateral olfactory tract usher substance (LOTUS), which are completely different novel drug target from existing drugs, and the possibility of endogenous inhibitors of PirB. PirB expressed in neurons is a negative regulator of neuronal plasticity, as loss or inhibition of PirB increases neuronal plasticity, leading to increased spine density and improved cognitive function. Furthermore, PirB is known to function as a receptor for Aβ, leading to reduced neuronal plasticity and cell death. These findingss suggest that PirB can be positioned as a novel drug target for the treatment of AD. The neuronal circuit-forming factor LOTUS, which binds to PirB and functions as an endogenous antagonist, has been shown to inhibit the neurotoxic effects of Aβ mediated by PirB. Namely, LOTUS is an endogenous molecule that inhibits Aβ receptor function of PirB and may have medicinal effects against Aβ pathology.},
}

Humans
Animals
*Alzheimer Disease/drug therapy/metabolism
Amyloid beta-Peptides/metabolism
Neuronal Plasticity
*Receptors, Immunologic/metabolism/physiology

@article {pmid40886864,
year = {2025},
author = {Su, Y and Shang, C and Cao, B and Ma, H and Wang, P and Song, J and Xie, Z and Zhang, Z},
title = {Ferulic acid derived from Huanshaodan improves cognitive deficits in Alzheimer's disease model through regulating APP proteolytic processing via downregulation of SIRT2 expression.},
journal = {Journal of ethnopharmacology},
volume = {},
number = {},
pages = {120508},
doi = {10.1016/j.jep.2025.120508},
pmid = {40886864},
issn = {1872-7573},
abstract = {Huanshaodan (HSD) is a Traditional Chinese Medicine Compound Prescription, traditionally used in the clinical treatment of Alzheimer's disease (AD) in China. Nevertheless, its bioactive constituents and mechanistic basis remain poorly understood.

AIM OF THE STUDY: To identify the components derived from HSD that inhibit SIRT2 and investigate the underlying mechanisms in mitigating AD pathogenesis.

MATERIALS AND METHODS: A luciferase reporter gene assay was employed to screen HSD for components that downregulate SIRT2 expression. The neuroprotective effects and the mechanisms of the screened component, ferulic acid (FA), was evaluated both in SAMP8 mice and HT22-APPswe cell using behavioral tests, H&E, immunohistochemistry, transmission electron microscopy, ELISA, MTT, Western blot, RT-qPCR, immunofluorescence and Co-immunoprecipitation, to assess its effect on SIRT2 expression, SIRT2-APP interaction, as well as the expression of proteins associated with APP proteolytic processing. SIRT2-overexpressing plasmids were transfected to assess FA's neuroprotection via SIRT2 modulation.

RESULTS: As a component in HSD, FA inhibited SIRT2 promoter-driven transcription, ameliorated cognitive deficits, protected neuronal and synaptic structures, reduced Aβ deposition in SAMP8 mice and Aβ level in HT22-APPswe cells. FA suppressed SIRT2 expression, inhibited SIRT2-APP interaction, modulated the expression levels of proteins involved in APP proteolytic processing, namely ADAM10, sAPPα, BACE1, sAPPβ, and CTFα in vitro and in vivo. Notably, the regulatory effects of FA on APP proteolytic processing in HT22-APPswe cells were completely abolished upon SIRT2 overexpression.

CONCLUSIONS: This study demonstrates that FA is an active component in HSD that mitigates AD pathology, potentially by modulating APP proteolytic processing through SIRT2 downregulation.},
}

@article {pmid40886227,
year = {2025},
author = {da Silva, AMP and Falcão, L and Ribeiro Gonçalves, O and Virgilio Ribeiro, F and Machado Magalhães, PL and Lee Han, M and Łajczak, P and Letícia de Bastos Maximiano, M and Cal, H and de Souza Franco, E and de Sousa Maia, MB},
title = {Brexpiprazole for the Treatment of Agitation in Older Adults with Alzheimer's Disease: A Systematic Review, Bayesian Meta-analysis, and Meta-regression.},
journal = {CNS drugs},
volume = {},
number = {},
pages = {},
pmid = {40886227},
issn = {1179-1934},
abstract = {BACKGROUND: Agitation is a common and distressing neuropsychiatric symptom in Alzheimer's disease (AD), affecting up to half of patients and contributing to faster cognitive decline and caregiver burden. Brexpiprazole, a serotonin-dopamine modulator, has been evaluated for this indication, but uncertainties remain regarding its efficacy, safety, and appropriate use in older adults.

OBJECTIVE: We aimed to assess the efficacy and safety of brexpiprazole for the treatment of agitation in older adults with AD through a systematic review and meta-analysis of randomized controlled trials (RCTs).

METHODS: Following the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) 2020 guidelines and the Cochrane Handbook, we included RCTs comparing brexpiprazole (0.5-3 mg/day) with placebo in older adults with a clinical diagnosis of AD. Primary outcomes were agitation severity (measured using the Cohen-Mansfield Agitation Inventory [CMAI]), clinical impression (clinical global impression-severity scale [CGI-S]), neuropsychiatric symptoms (Neuropsychiatric Inventory [NPI]), and adverse events. Risk ratios (RR) and mean differences (MD) with 95% confidence intervals (CI) were pooled using a random-effects model. Random-effects meta-analyses were performed using frequentist and Bayesian models in R (version 4.3.0).

RESULTS: A total of five RCTs (N = 1770) met the inclusion criteria. Brexpiprazole was associated with a modest reduction in agitation CMAI (MD - 5.79; 95% CI - 9.55 to - 2.04; prediction interval: - 14.07 to 2.49) and improved CGI-S scores (MD - 0.23; 95% CI - 0.32 to - 0.13; prediction interval: - 0.39 to - 0.06). No significant differences were found in NPI scores. Adverse events such as extrapyramidal symptoms and daytime somnolence occurred more frequently with brexpiprazole but with wide and nonsignificant intervals. Meta-regression did not identify dose or duration as effect modifiers.

CONCLUSIONS: Brexpiprazole may offer modest short-term benefits for agitation in AD without cognitive worsening, but safety signals remain imprecise. However, prediction intervals indicate considerable uncertainty, and its use should be individualized and closely monitored. Future trials should prioritize long-term outcomes and patient-centered measures.

CRD 42025646060.},
}

@article {pmid40885501,
year = {2025},
author = {Rahamouz-Haghighi, S and Akaberi, M and Emami, SA and Tayarani-Najaran, Z},
title = {Biochemical Profiling and Protective Effects of Scutellaria litwinowii Against AlCl3-Induced Neurotoxicity in PC12 Cells.},
journal = {Journal of ethnopharmacology},
volume = {},
number = {},
pages = {120504},
doi = {10.1016/j.jep.2025.120504},
pmid = {40885501},
issn = {1872-7573},
abstract = {Scutellaria litwinowii Bornm. & Sint., native to Iran, belongs to the Lamiaceae family, Scutellaria species are widely used in traditional medicine for treating inflammation, infections, and Neurological diseases.

AIM OF THE STUDY: This research aimed to assess the neuroprotective effects of S. litwinowii fractions, focusing on anti-acetylcholinesterase (anti-AChE), antioxidant, and anti-apoptotic activities.

MATERIALS AND METHODS: Oxidative stress and apoptosis were created utilizing aluminum chloride (AlCl3) in PC12 cells. The neuroprotective effect was assessed using resazurin assays, while reactive oxygen species (ROS), AChE and glutathione (GSH) were assessed using DCF-DA and Ellman's Reagent, respectively. Apoptotic cells, and lactate dehydrogenase (LDH) release were also evaluated. Western blot analysis detected the expression of β-Catenin, Survivin, and phosphorylated SAPK JNK/SAPKJNK. A dichloromethane (DCM) root fraction underwent HPLC and LC-ESI-MS profiling to identify active anti-AChE compounds.

RESULTS: 48 h treatment with 5 mM AlCl3 decreased cell viability by 27%. Pretreatment with the DCM fraction at 6.25 and 12.5 μg/ml significantly improved viability, reduced ROS and LDH release, and prevented GSH depletion, comparable to the antioxidant N-acetylcysteine (p < 0.001). At a 12.5 μg/ml, the DCM fraction inhibited AChE activity by 63.61%, while 12.5 μM baicalein showed 59.11% inhibition. The DCM fraction and baicalein significantly reduced AlCl3-induced apoptosis (p < 0.001), increased of β-Catenin, Survivin expression and decreased p-JNK/JNK ratio (p < 0.001). In the active time window, baicalein and wogonin were detected.

CONCLUSION: This research suggests that S. litwinowii and baicalein may serve as protective agents against oxidative stress and apoptosis-related cell damage.},
}

@article {pmid40885031,
year = {2025},
author = {Majie, A and Karmakar, V and Ghosh, A and Chakraborty, S and Apurva, and Layek, B and Gorain, B},
title = {Advanced intranasal peptide delivery systems for improved management of Alzheimer's disease.},
journal = {Biomaterials advances},
volume = {178},
number = {},
pages = {214474},
doi = {10.1016/j.bioadv.2025.214474},
pmid = {40885031},
issn = {2772-9508},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder that leads to cognitive decline, memory loss, and impairment in daily functioning, making up nearly 60 % of all dementia cases. Current treatments primarily manage symptoms rather than address the disease itself, underscoring the need for more effective solutions. Therapeutic peptides have emerged as promising candidates, targeting critical pathological processes in AD. Additionally, intranasal delivery offers significant advantages, including non-invasiveness, enhanced stability, rapid absorption, and the ability to bypass the blood-brain barrier. This review explores the potential of intranasal peptide delivery for AD treatment, beginning with an overview of the disease's mechanisms and existing therapies. We discuss the challenges of targeting the brain, examine nose-to-brain delivery pathways, and highlight recent advancements in delivery techniques, including the role of nanoparticles in improving efficacy. Our goal is to encourage further research into these innovative delivery strategies that could improve patient compliance and treatment outcomes. While preclinical studies indicate substantial promise, advancing these findings into clinical applications remains crucial to overcoming drug delivery challenges and ensuring long-term safety.},
}

@article {pmid40884977,
year = {2025},
author = {Kong, X and Yu, Z and Sun, Q and Liu, Y and Yin, ZZ},
title = {An integrative and efficient microbiosensor for β-amyloid42 based on a molecularly imprinted layer coordinating built-in hemin on the acupuncture needle.},
journal = {Bioelectrochemistry (Amsterdam, Netherlands)},
volume = {167},
number = {},
pages = {109095},
doi = {10.1016/j.bioelechem.2025.109095},
pmid = {40884977},
issn = {1878-562X},
abstract = {Monitoring beta-amyloid1-42 (Aβ42) is vital and challenging, which is a typical biomarker of Alzheimer's disease. Here, a novel electrochemical microbiosensor is developed to detect Aβ42 on an acupuncture needle. Hemin is well known for its characteristics, including its ability to self-assemble on single-walled carbon nanotube (SWCNT), the molecular interaction with Aβ42, and the intrinsic electroactive signal. These properties are exploited to anchor and respond to Aβ42 after integrating a molecularly imprinted surface polymer (SMIP). The SMIP layer of polydopamine/poly (ionic liquid) can be prepared by electropolymerization on an acupuncture needle microelectrode (ANME), which undergoes growth and formation of a polymeric structure around the anchored Aβ42. Interestingly, the imprinted cavities express a fluent signal of built-in hemin after eluting the templates, and show a highly selective and sensitive hindrance response for the recombined Aβ42. Under optimized conditions, the microbiosensor displays a linear range of 100 to 1 × 10[10] fM with a limit of detection of 0.05 fM. There are development and advances for the discipline of electroanalysis after comparing the technique and important indicators with the electrochemical biosensors reported of Aβ42. The microbiosensor also exhibited excellent selectivity, good stability, and reproducibility, which was effectively used to detect Aβ42 in real spiked samples. The improved behavior of the developed microbiosensor can be attributed to its superficial highly matched imprinted cavities, built-in hemin label, and electronic barrier without signal of the nonimprinted surface to outside molecules. This microbiosensor has a scientific and reference value for directly sensing non-electroactive biomarkers, functionalizing microelectrodes, and electron transport cavities. It would also be amazing if this new microbiosensor could combine with the unclear and magical property of acupuncture in the treatment of neurological disorders.},
}

@article {pmid40884807,
year = {2025},
author = {Ding, MR and Xia, CY and Qu, YJ and Zhang, LM and Zhang, MX and Zhen, RR and Zhang, T and Chen, JF and Hu, B and An, HM},
title = {Identification of Flavonoid Compounds in Treating Alzheimer's Disease Based on Network Medicine Framework Strategy.},
journal = {The American journal of Chinese medicine},
volume = {},
number = {},
pages = {1-32},
doi = {10.1142/S0192415X25500806},
pmid = {40884807},
issn = {1793-6853},
abstract = {Alzheimer's disease (AD) currently lacks effective therapeutics, but blood-brain-barrier-penetrating flavonoids show promising therapeutic potential. To address this critical need, we employed a novel network medicine framework to systematically identify flavonoid compounds for AD therapy by quantifying their network proximity to AD targets. Our systematic screening identified 48 potential anti-AD flavonoids, of which luteolin, quercetin, apigenin (API), and baicalein demonstrated significant neuroprotective effects in A[Formula: see text]25-35-induced rat pheochromocytoma (PC12) cell models. Of these, API emerged as the most promising candidate. A network pharmacological analysis revealed that API likely exerts its anti-AD effects through modulating apoptosis and inflammatory response, and AKT1 and NFKBIA were identified as key therapeutic targets. Experimental validation demonstrated that API treatment impeded the H2O2-induced decline in the mitochondrial membrane potential of PC12 cells, suppressed apoptosis, and mitigated neuronal damage. Furthermore, API downregulated the AKT/NF-[Formula: see text]B signal pathway, promoted microglial M2 polarization, and attenuated LPS-induced neuroinflammation in BV2 cells. API also alleviated the toxic effects of M1 microglia on neurons. This network-based screening strategy provides an innovative approach for developing new AD therapeutics.},
}

@article {pmid40883746,
year = {2025},
author = {Holmes, BB and Weigel, TK and Chung, JM and Kaufman, SK and Apresa, BI and Byrnes, JR and Kumru, KS and Vaquer-Alicea, J and Gupta, A and Rose, IVL and Zhang, Y and Nana, AL and Alter, D and Grinberg, LT and Spina, S and Leung, KK and Miller, BL and Condello, C and Kampmann, M and Seeley, WW and Coutinho-Budd, JC and Wells, JA},
title = {β-Amyloid induces microglial expression of GPC4 and APOE leading to increased neuronal tau pathology and toxicity.},
journal = {Molecular neurodegeneration},
volume = {20},
number = {1},
pages = {96},
pmid = {40883746},
issn = {1750-1326},
support = {BrightFocus Foundation//BrightFocus Foundation/ ; Shenandoah Community Foundation//Shenandoah Community Foundation/ ; Brain Institute, University of Virginia//Brain Institute, University of Virginia/ ; 1K08NS133290/NS/NINDS NIH HHS/United States ; R01NS121101/NS/NINDS NIH HHS/United States ; R35GM122451/GM/NIGMS NIH HHS/United States ; RF1AG061874/NH/NIH HHS/United States ; K24AG053435/NH/NIH HHS/United States ; P01AG019724/NH/NIH HHS/United States ; P30AG062422/NH/NIH HHS/United States ; U19AG063911/NH/NIH HHS/United States ; U01AG057195/NH/NIH HHS/United States ; ZEN-22-969903/ALZ/Alzheimer's Association/United States ; },
abstract = {UNLABELLED: To define how Aβ pathology alters microglia function in Alzheimer’s disease, we profiled the microglia surfaceome following treatment with Aβ fibrils. Our findings reveal that Aβ-associated human microglia upregulate Glypican 4 (GPC4), a GPI-anchored heparan sulfate proteoglycan (HSPG). Glial GPC4 expression exacerbates motor deficits and reduces lifespan in a Drosophila amyloidosis model, implicating GPC4 in a toxic neurodegenerative program. In cell culture, GPC4 enhances microglia phagocytosis of tau aggregates, and shed GPC4 can act in trans to facilitate tau aggregate uptake and seeding in neurons. Additionally, our data demonstrate that GPC4-mediated effects are amplified in the presence of APOE. In human Alzheimer’s disease brain, microglial GPC4 expression surrounding Aβ plaques correlates with neuritic tau pathology, supporting a pathological link between amyloid, GPC4, and tau. These studies define a mechanistic pathway by which Aβ primes microglia to promote tau pathology via HSPGs and APOE.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13024-025-00883-4.},
}

@article {pmid40883512,
year = {2025},
author = {Hanumanthappa, D and Kumar, BS and Shajan, SRO and Sadashivappa, NM and Walikar, SK and Hosur Dinesh, BG and Ganjipete, S and Kunjiappan, S and Theivendren, P and Chidamabaram, K and Ammunje, DN and Pavadai, P},
title = {Computational insights and experimental breakthroughs in identifying next-generation acetylcholinesterase inhibitors.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {31901},
pmid = {40883512},
issn = {2045-2322},
mesh = {Animals ; *Cholinesterase Inhibitors/pharmacology/chemistry ; *Alzheimer Disease/drug therapy/pathology ; Rats ; Molecular Docking Simulation ; *Acetylcholinesterase/metabolism/chemistry ; Neuroprotective Agents/pharmacology/chemistry ; Male ; Nanoparticles/chemistry ; Brain/drug effects/pathology ; Disease Models, Animal ; Molecular Dynamics Simulation ; Humans ; },
abstract = {The study aimed to identify the potential acetylcholinesterase (AChE) inhibitors for effective Alzheimer's treatment from existing FDA-approved drugs through a drug repurposing technique via computational tools. Further, to evaluate the anti-Alzheimer's potency of the identified drug with the help of a suitable drug delivery system through in vivo pharmacological studies. The molecular docking and dynamics simulation studies indicated that letrozole has a significant binding affinity of -9.6 kcal/mol and a better interaction with AChE. The physicochemical properties of letrozole-encapsulated solid lipid nanoparticles (L-SLNs) were characterized and confirmed. Initially, acute toxicity tests of L-SLNs were performed according to OECD 423 guidelines. Biochemical studies revealed that L-SLNs significantly decreased brain Acetylcholine esterase activity induced by scopolamine, but L-SLNs significantly increased AChE activity compared to the Shaam control group. Histopathological evaluation of brain regions revealed significant insights into the neuroprotective potential of L-SLNs in an Alzheimer's disease (AD) rat model. Treatment with L-SLNs demonstrated dose-dependent neuroprotection across all studied brain regions. At a low dose of L-SLNs (2.5 mg/kg), neuronal and glial cells in the cortical and hippocampal regions showed improved regularity, although some disorganization persisted. At a mid-dose of L-SLNs (5 mg/kg), the histopathological architecture further normalized, with neurons and glial cells exhibiting regular arrangement and morphology akin to normal cells. The high dose of L-SLNs (10 mg/kg) provided the most significant protection, with neuronal and glial cells displaying near-normal arrangement and morphology in the cortical, hippocampal, and Substantia Nigra regions. This study highlights the importance of SLNs-based drug delivery systems in improving the efficacy of existing therapeutic agents in neurodegenerative conditions.},
}

Animals
*Cholinesterase Inhibitors/pharmacology/chemistry
*Alzheimer Disease/drug therapy/pathology
Rats
Molecular Docking Simulation
*Acetylcholinesterase/metabolism/chemistry
Neuroprotective Agents/pharmacology/chemistry
Male
Nanoparticles/chemistry
Brain/drug effects/pathology
Disease Models, Animal
Molecular Dynamics Simulation
Humans

@article {pmid40882479,
year = {2025},
author = {Chen, T and Li, X},
title = {ResGSNet: Enhanced local attention with Global Scoring Mechanism for the early detection and treatment of Alzheimer's Disease.},
journal = {Computers in biology and medicine},
volume = {197},
number = {Pt A},
pages = {110951},
doi = {10.1016/j.compbiomed.2025.110951},
pmid = {40882479},
issn = {1879-0534},
abstract = {Recently, Transformer has been widely used in medical imaging analysis for its competitive potential when given enough data. However, Transformer conducts attention on a global scale by utilizing self-attention mechanisms across all input patches, thereby requiring substantial computational power and memory, especially when dealing with large 3D images such as MRI images. In this study, we proposed Residual Global Scoring Network (ResGSNet), a novel architecture combining ResNet with Global Scoring Module (GSM), achieving high computational efficiency while incorporating both local and global features. First, our proposed GSM utilized local attention to conduct information exchange within local brain regions, subsequently assigning global scores to each of these local regions, demonstrating the capability to encapsulate local and global information with reduced computational burden and superior performance compared to existing methods. Second, we utilized Grad-CAM＋＋ and the Attention Map to interpret model predictions, uncovering brain regions related to Alzheimer's Disease (AD) Detection. Third, our extensive experiments on the ADNI dataset show that our proposed ResGSNet achieved satisfactory performance with 95.1% accuracy in predicting AD, a 1.3% increase compared to state-of-the-art methods, and 93.4% accuracy for Mild Cognitive Impairment (MCI). Our model for detecting MCI can potentially serve as a screening tool for identifying individuals at high risk of developing AD and allow for early intervention. Furthermore, the Grad-CAM＋＋ and Attention Map not only identified brain regions commonly associated with AD and MCI but also revealed previously undiscovered regions, including putamen, cerebellum cortex, and caudate nucleus, holding promise for further research into the etiology of AD.},
}

@article {pmid40882298,
year = {2025},
author = {Sobha, A and Krishnan, L and Shaik, S and Pai, A and Purushothaman, J and Alaganandam, K and Somappa, SB},
title = {Targeting Alzheimer's pathology: Tetralone- and thiochromanone-based benzyl pyridinium derivatives as promising multi-target-directed ligands.},
journal = {Bioorganic & medicinal chemistry},
volume = {130},
number = {},
pages = {118369},
doi = {10.1016/j.bmc.2025.118369},
pmid = {40882298},
issn = {1464-3391},
abstract = {The lack of therapeutics that can fully halt the progression of Alzheimer's disease (AD) has prompted us to design and synthesize a series of tetralone/thiochromanone-based benzyl pyridinium salts (4a-4s) aimed at modulating multiple pathological targets associated with AD. Preliminary screening for cholinesterase and monoamine oxidase inhibition identified compounds 4e and 4g as the most potent inhibitors (AChE IC50: 2.17 ± 0.13 μM and 2.29 ± 0.15 μM; MAO-B IC50: 0.89 ± 0.07 μM and 0.92 ± 0.16 μM, respectively). Both compounds also demonstrated anti-neuroinflammatory activity by reducing pro-inflammatory cytokines (TNF-α and IL-6) and downregulating COX-2 and NF-κB signalling pathways. Additionally, 4e exhibited significant ROS scavenging ability by mitigating oxidative stress and conferred neuroprotection in SH-SY5Y cells by attenuating Aβ1-42-induced mitochondrial dysfunction and apoptosis. Collectively, these findings position compound 4e as a promising multi-target-directed ligand (MTDL) for the treatment of AD.},
}

@article {pmid40882223,
year = {2025},
author = {Jiang, X and Wu, L and Zhou, R and Quan, M and Xiang, X},
title = {Galanthamine promotes neuronal differentiation and neurite outgrowth of neural progenitor/stem cells by up-regulating IGF-2.},
journal = {Biochemistry and cell biology = Biochimie et biologie cellulaire},
volume = {},
number = {},
pages = {},
doi = {10.1139/bcb-2025-0058},
pmid = {40882223},
issn = {1208-6002},
abstract = {Galanthamine, an alkaloid derived from the Amaryllidaceae family, serves as an acetylcholinesterase inhibitor. Due to its central cholinergic properties, this compound is being actively studied as a potential treatment for Alzheimer's disease. However, the broader scope of its biological effects remains poorly understood. In this study, we explored the therapeutic potential of galanthamine in promoting neuronal differentiation and enhancing neurite outgrowth in neural stem and progenitor cells (NSPCs). Our detailed analysis demonstrated notable changes in neuronal morphology and complexity during maturation following galanthamine exposure. Notably, the compound significantly increased the proportion of neurons with multiple neurites, indicating its ability to stimulate neurite formation and foster the development of complex neuronal networks. Furthermore, galanthamine treatment led to a marked rise in the number of mature-appearing neurons, distinguished by elongated and intricate dendrites, highlighting its potential to enhance neural plasticity and repair mechanisms. Importantly, we also identified that galanthamine facilitates neuronal differentiation in NSPCs by upregulating the IGF2 signaling pathway. Collectively, these findings provide valuable insights into galanthamine's role in Alzheimer's disease and emphasize its promise as a therapeutic agent for this neurodegenerative disorder.},
}

@article {pmid40881368,
year = {2025},
author = {Zhao, J and Dong, X and Liu, B and Peng, Y and Yao, Z},
title = {Cognitive function enhancement in Alzheimer's disease through traditional Chinese medicine rehabilitation nursing: meta-analysis.},
journal = {Frontiers in psychiatry},
volume = {16},
number = {},
pages = {1631589},
doi = {10.3389/fpsyt.2025.1631589},
pmid = {40881368},
issn = {1664-0640},
abstract = {Alzheimer's disease (AD) manifests as progressive cognitive deterioration with significant impact on patient independence and quality of life. While conventional treatments offer limited efficacy, Traditional Chinese Medicine (TCM) rehabilitation nursing presents a complementary approach deserving systematic evaluation. To synthesize existing evidence on the efficacy of TCM rehabilitation nursing for cognitive enhancement in AD through comprehensive meta-analysis. We conducted systematic searches across multiple electronic databases (PubMed, Embase, CNKI, Wanfang, and VIP) for controlled studies published from 2010 to present examining TCM rehabilitation nursing interventions for AD patients. Methodological quality was assessed using the Cochrane Risk of Bias 2.0 tool. Primary outcomes included Mini-Mental State Examination (MMSE), Activities of Daily Living (ADL), and treatment efficacy rates. Statistical synthesis employed RevMan 5.3 with random or fixed effects models based on heterogeneity assessment. Nine eligible studies encompassing 864 participants (432 intervention, 432 control) met inclusion criteria. Meta-analysis revealed significantly improved cognitive function in the TCM rehabilitation nursing group compared to conventional care, with MMSE scores showing substantial enhancement (mean difference = 4.63, 95% confidence interval: 3.74-5.53, P<0.00001). Treatment response analysis demonstrated higher rates of marked clinical improvement (risk ratio = 2.78, 95% CI: 1.65-4.70, P=0.0001) and substantially reduced treatment failure rates (85% reduction, P<0.00001). Though ADL scores showed positive trends, these did not reach statistical significance (P=0.07). TCM rehabilitation nursing demonstrates significant efficacy in enhancing cognitive function and treatment outcomes in AD patients. These findings support its integration into comprehensive care strategies, though additional research with standardized protocols is warranted for optimal implementation.},
}

@article {pmid40881206,
year = {2025},
author = {Parchwani, D and Singh, R and Patel, D},
title = {Biological and translational attributes of mitochondrial DNA copy number: Laboratory perspective to clinical relevance.},
journal = {World journal of methodology},
volume = {15},
number = {3},
pages = {102709},
doi = {10.5662/wjm.v15.i3.102709},
pmid = {40881206},
issn = {2222-0682},
abstract = {The mitochondrial DNA copy number (mtDNAcn) plays a vital role in cellular energy metabolism and mitochondrial health. As mitochondria are responsible for adenosine triphosphate production through oxidative phosphorylation, maintaining an appropriate mtDNAcn level is vital for the overall cellular function. Alterations in mtDNAcn have been linked to various diseases, including neurodegenerative disorders, metabolic conditions, and cancers, making it an important biomarker for understanding the disease pathogenesis. The accurate estimation of mtDNAcn is essential for clinical applications. Quantitative polymerase chain reaction and next-generation sequencing are commonly employed techniques with distinct advantages and limitations. Clinically, mtDNAcn serves as a valuable indicator for early diagnosis, disease progression, and treatment response. For instance, in oncology, elevated mtDNAcn levels in blood samples are associated with tumor aggressiveness and can aid in monitoring treatment efficacy. In neurodegenerative diseases such as Alzheimer's and Parkinson's, altered mtDNAcn patterns provide insights into disease mechanisms and progression. Understanding and estimating mtDNAcn are critical for advancing diagnostic and therapeutic strategies in various medical fields. As research continues to uncover the implications of mtDNAcn alterations, its potential as a clinical biomarker is likely to expand, thereby enhancing our ability to diagnose and manage complex diseases.},
}

@article {pmid40880849,
year = {2025},
author = {Fu, L and Luo, T and Hao, Z and Pan, Y and Xin, W and Zhang, L and Lai, Z and Zhang, H and Liu, H and Wei, W},
title = {Exploring novel roles of lipid droplets and lipid metabolism in regulating inflammation and blood-brain barrier function in neurological diseases.},
journal = {Frontiers in neuroscience},
volume = {19},
number = {},
pages = {1603292},
doi = {10.3389/fnins.2025.1603292},
pmid = {40880849},
issn = {1662-4548},
abstract = {The blood-brain barrier (BBB) is a critical structure that maintains the brain's homeostasis by regulating the transport of molecules and protecting it from harmful substances. However, in neurological diseases such as ischemic stroke, Alzheimer's disease, Parkinson's disease, and multiple sclerosis, the integrity and function of the BBB can be significantly compromised. In these conditions, BBB disruption leads to increased permeability, which facilitates neuroinflammation, exacerbates neuronal damage, and accelerates disease progression. Recent research has highlighted the potential of lipid-based carriers, including liposomes and lipid droplets (LDs), in modulating the BBB's integrity and function in various neurological diseases. Liposomes, with their ability to cross the BBB via mechanisms such as receptor-mediated transcytosis and carrier-mediated transport, are emerging as promising vehicles for the targeted delivery of therapeutic agents to the brain. These properties allow liposomes to effectively reduce infarct size and promote neuroprotection in ischemic stroke, as well as deliver drugs in the treatment of neurodegenerative diseases. Furthermore, LDs-dynamic regulators of lipid metabolism and cellular energy-play an essential role in maintaining cellular homeostasis, particularly during periods of stress when BBB function is compromised. These LDs help sustain cellular energy needs and modulate inflammatory responses, which are key factors in maintaining BBB integrity. Surface modifications of liposomes can further enhance their targeting efficiency, enabling them to selectively bind to specific brain cell types, including neurons, astrocytes, and microglia. This customization improves the precision of therapeutic delivery and supports the development of more tailored treatments. However, challenges such as immune responses, rapid clearance, and complement activation-related toxicity continue to hinder the broader application of liposomes and LDs in clinical settings. This review will focus on the roles of liposomes and LDs in regulating BBB integrity across a range of neurological diseases, discussing their potential for targeted drug delivery, neuroprotection, and the modulation of neuroinflammation. Additionally, we will explore the strategies being developed to address the limitations that currently restrict their clinical use.},
}

@article {pmid40879893,
year = {2025},
author = {Serio, MA and Dethloff, DR and Curry, GC and Beesley, ML and Shekoohi, S and Kaye, AD},
title = {Emerging Concepts in Diagnosis, Pathologic Features, and Treatment of Limbic-Predominant Amnestic Neurodegenerative Syndrome (LANS): A Narrative Review.},
journal = {Advances in therapy},
volume = {},
number = {},
pages = {},
pmid = {40879893},
issn = {1865-8652},
abstract = {INTRODUCTION: Neurodegenerative disorders (NDs) are characterized by progressive loss of function and destruction of the central and peripheral nervous systems. These disorders result in devastating irreversible cognitive decline and affect millions of people worldwide. Alzheimer's disease (AD) is a common cause of dementia that increases in incidence with increasing age. Limbic-predominant amnestic neurodegenerative syndrome (LANS) is another common etiology of amnestic symptoms and often affects the "oldest-old" of the population. The two disorders share many similarities yet are clearly pathologically distinct. Establishing robust classifications to distinguish these two disorders is key to future management and care of an aging population. The present investigation explored the pathophysiology of neurodegenerative disorders (NDs), specifically Alzheimer's disease (AD), limbic-predominant amnestic neurodegenerative syndrome (LANS), and limbic-predominant age-related TDP-43 encephalopathy (LATE).

METHODS: We performed a comprehensive narrative review of the literature, covering studies from database inception through November 2024. We searched PubMed/MEDLINE, Embase, Web of Science, Cochrane Library, and Google Scholar for relevant publications. We also reviewed reference lists of key articles. Two authors independently screened titles/abstracts for relevance and extracted data on study design, patient population, neuropathologic findings, imaging/biomarker methods, and clinical features. Discrepancies were resolved by discussion. This review synthesized findings on the need for LANS criteria and compared LANS to AD and LATE across clinical, imaging, pathologic, and biomarker domains.

RESULTS: A comprehensive analysis of the key pathologic features and distinctions among selected neurodegenerative syndromes was carried out using peer-reviewed literature.

CONCLUSIONS: Recently proposed clinical criteria for LANS are a milestone in the characterization and further treatment of neurodegenerative disease. Understanding the minute differences in pathophysiology among various NDs allows for pioneering more targeted disease-modifying treatments. This narrative review provides concise reflection between AD and other NDs involving LATE-NC changes.},
}

@article {pmid40879814,
year = {2025},
author = {Lei, J and Li, J and Wu, W and Xiong, R and Liu, Y and Tang, Y},
title = {Neuroprotective effects of Yangming-Kaixin-Yizhi formula in Alzheimer's disease: dual regulation of PI3K/Akt and p38 MAPK signaling via network pharmacology and experimental approaches.},
journal = {Metabolic brain disease},
volume = {40},
number = {7},
pages = {254},
pmid = {40879814},
issn = {1573-7365},
support = {2024ZYQN017//Joint Project of Chongqing Health Commission and Science and Technology Bureau/ ; 82405150//National Natural Science Foundation of China/ ; 2025ZNSFSC0740//Sichuan Provincial Science and Technology Support Program/ ; },
mesh = {Animals ; *Alzheimer Disease/drug therapy/metabolism ; *Neuroprotective Agents/pharmacology/therapeutic use ; *Drugs, Chinese Herbal/pharmacology/therapeutic use ; Mice ; *p38 Mitogen-Activated Protein Kinases/metabolism ; *Proto-Oncogene Proteins c-akt/metabolism ; Network Pharmacology/methods ; Phosphatidylinositol 3-Kinases/metabolism ; Mice, Transgenic ; Male ; Signal Transduction/drug effects ; *MAP Kinase Signaling System/drug effects ; Molecular Docking Simulation ; Disease Models, Animal ; },
abstract = {As a neurodegenerative disease characterized by progressive cognitive decline, the pathogenesis of Alzheimer's disease (AD) is still poorly understood, and there is no effective cure currently available. Traditional Chinese medicine (TCM) prescription Yangming-Kaixin-Yizhi formula (YKY) has been clinically applied for the treatment of memory loss related disorders for more than 300 years with remarkable efficacy, but its pharmacological mechanism remains unclear. This study aimed to investigate the therapeutic effects of YKY on AD and its molecular mechanisms. We evaluated YKY's ameliorative effects on the AD phenotype in 3xTg-AD mice using the Morris water maze, histopathological staining, and immunofluorescence assays. The major chemical components of YKY were identified by UPLC-QTOF-MS/MS. Network pharmacology was employed to analyze the molecular mechanisms of YKY in treating AD, followed by validation of its regulatory effects on key pathways through immunofluorescence experiments and molecular docking. The results showed that YKY could significantly improve learning and memory ability, neuronal loss, β-amyloid deposition and glial cell activation in 3xTg-AD mice. 48 chemical components were identified from YKY, and network pharmacology analysis of them showed that YKY may improve AD by regulating apoptosis, PI3K/Akt and MAPK pathways. Immunofluorescence and molecular docking results also confirmed the regulatory effect of YKY on key targets of apoptosis, PI3K/Akt and p38 MAPK pathways. In conclusion, by integrating animal experiments and network pharmacology, the present study revealed the mechanism of YKY in inhibiting neuronal apoptosis by regulating PI3K/Akt and p38 MAPK pathways, which providing modern scientific evidence for the traditional clinical application of YKY.},
}

Animals
*Alzheimer Disease/drug therapy/metabolism
*Neuroprotective Agents/pharmacology/therapeutic use
*Drugs, Chinese Herbal/pharmacology/therapeutic use
Mice
*p38 Mitogen-Activated Protein Kinases/metabolism
*Proto-Oncogene Proteins c-akt/metabolism
Network Pharmacology/methods
Phosphatidylinositol 3-Kinases/metabolism
Mice, Transgenic
Male
Signal Transduction/drug effects
*MAP Kinase Signaling System/drug effects
Molecular Docking Simulation
Disease Models, Animal

@article {pmid40879672,
year = {2025},
author = {Farajpour, N and Soraya, H},
title = {Neuroprotective effects of ivermectin on Alzheimer's model induced by streptozotocin in rats.},
journal = {Neurodegenerative disease management},
volume = {},
number = {},
pages = {1-9},
doi = {10.1080/17582024.2025.2554374},
pmid = {40879672},
issn = {1758-2032},
abstract = {BACKGROUND: Alzheimer's disease is a neurodegenerative condition characterized by memory deficits and cognitive decline. Ivermectin, an antiparasitic agent, has shown neuroprotective effects. The present study was conducted to determine the protective effects of ivermectin in a streptozocin-induced Alzheimer's model in rats.

METHODS: Alzheimer's model was induced by bilateral intracerebroventricular injection of streptozocin (3 mg/kg BW, 2 doses). Ivermectin was administered intraperitoneally at a dose of 2 mg/kg. On day 19, after behavioral memory and learning tests, the samples were collected for histological and enzymatic studies.

RESULTS: Ivermectin reduced the histopathological changes, including pyknotic and dead neurons and the accumulation of Aβ plaques. Ivermectin administration also reduced serum (p < 0.0001) and brain tissue (p < 0.01) acetylcholinesterase activity as well as improved learning (p < 0.05) and spatial memory (p < 0.0001).

CONCLUSIONS: Ivermectin demonstrates protective effects in the STZ-induced Alzheimer's model by reducing pathological changes and Aβ plaques, acetylcholinesterase activity, as well as improving memory and learning.},
}

@article {pmid40879647,
year = {2025},
author = {Fabrik, I and Kupcik, R and Fabrikova, D and Chvojkova, M and Holubova, K and Hakenova, K and Horak, M and Soukup, J and Manethova, M and Rusina, R and Matej, R and Ryska, A and Soukup, O},
title = {Memantine Administration Enhances Glutamatergic and GABAergic Pathways in the Human Hippocampus of Alzheimer's Disease Patients.},
journal = {Proteomics},
volume = {25},
number = {15},
pages = {42-49},
doi = {10.1002/pmic.70006},
pmid = {40879647},
issn = {1615-9861},
support = {24-10026S//Grantová Agentura České Republiky/ ; 00064190//Ministerstvo Zdravotnictví Ceské Republiky/ ; 00179906//Ministerstvo Zdravotnictví Ceské Republiky/ ; Cooperatio-Neurosciences//Univerzita Karlova v Praze/ ; CZ.02.01.01/00/22_008/0004562//Ministerstvo Školství, Mládeže a Tělovýchovy/ ; LX22NPO5107//Ministerstvo Školství, Mládeže a Tělovýchovy/ ; },
mesh = {Humans ; *Memantine/pharmacology/administration & dosage/therapeutic use ; *Alzheimer Disease/metabolism/drug therapy/pathology ; *Hippocampus/metabolism/drug effects/pathology ; Male ; Female ; Aged ; *Glutamic Acid/metabolism ; Proteome/metabolism ; Proteomics/methods ; Aged, 80 and over ; Signal Transduction/drug effects ; Receptors, N-Methyl-D-Aspartate/metabolism/antagonists & inhibitors ; *Excitatory Amino Acid Antagonists/pharmacology ; Receptors, GABA/metabolism ; },
abstract = {One of the traditional treatments in Alzheimer's disease (AD) is administration of memantine, the NMDA receptor antagonist. However, the molecular mechanism of the complex memantine action and the impact on the hippocampal proteome in humans is unknown. In this study, hippocampal proteins extracted from formalin-fixed paraffin-embedded post mortem tissues obtained from healthy donors (n = 15), AD patients not treated with memantine (n = 11), and AD patients treated with memantine (n = 8) were investigated using tandem mass tag (TMT)-based quantitative proteomics. Memantine medication induced subtle but distinct changes in the hippocampal proteome in AD patients. Although it did not prevent the metabolic and physiologic decline associated with AD pathology, memantine administration upregulated several mitochondrially encoded proteins and mitigated the proteomic pattern of activated phagocytes. Furthermore, memantine specifically enhanced the expression of postsynaptic glutamatergic and GABAergic receptors and components of the respective pathways without affecting presynaptic proteome. This suggests that memantine treatment in AD patients not only alleviates excitotoxic stress by inhibiting NMDA receptor activity, but also triggers broader adaptations in the synaptic signaling and plasticity.},
}

Humans
*Memantine/pharmacology/administration & dosage/therapeutic use
*Alzheimer Disease/metabolism/drug therapy/pathology
*Hippocampus/metabolism/drug effects/pathology
Male
Female
Aged
*Glutamic Acid/metabolism
Proteome/metabolism
Proteomics/methods
Aged, 80 and over
Signal Transduction/drug effects
Receptors, N-Methyl-D-Aspartate/metabolism/antagonists & inhibitors
*Excitatory Amino Acid Antagonists/pharmacology
Receptors, GABA/metabolism

@article {pmid40879417,
year = {2025},
author = {Zheng, J and Liu, G and Wang, Q and Liang, Y},
title = {Insights into CYP450 Polymorphisms and Their Impact on Drug Metabolism in Alzheimer's Disease Therapy.},
journal = {Drug metabolism reviews},
volume = {},
number = {},
pages = {1-19},
doi = {10.1080/03602532.2025.2552786},
pmid = {40879417},
issn = {1097-9883},
abstract = {Alzheimer's disease (AD) is a complex neurodegenerative disorder that poses significant therapeutic challenges. Currently available treatments offer symptomatic relief but often yield suboptimal outcomes due to inter-individual variability in drug metabolism. Cytochrome P450 (CYP450) enzymes, particularly those exhibiting genetic polymorphisms, play a central role in the hepatic metabolism of many AD medications. This review focuses on the influence of CYP450 polymorphisms-specifically in CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4-on the pharmacokinetics, efficacy, and safety of approved anti-AD drugs. We discuss how variability in CYP450 expression and activity affects drug response, and examine the implications for adverse drug reactions, therapeutic failure, and dosage optimization. In addition, we evaluate current evidence for CYP450-mediated interactions with traditional Chinese medicines, which are increasingly used in complementary AD therapy. The potential for CYP450 genotyping and phenotyping to guide personalized treatment strategies is critically assessed. We argue that integrating pharmacogenomics into clinical practice may enhance therapeutic precision, reduce adverse outcomes, and improve quality of life in patients with AD. This review provides updated insight into the clinical significance of CYP450 polymorphisms in AD therapy and outlines future directions for personalized medicine approaches.},
}

@article {pmid40879416,
year = {2025},
author = {Chen, J and Lin, B and Seow, E and Kim, S and Bajaj, PS and Mattke, S},
title = {Prediction of infusion capacity to deliver Alzheimer's disease treatments in the United States relative to expected demand.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251372129},
doi = {10.1177/13872877251372129},
pmid = {40879416},
issn = {1875-8908},
abstract = {BackgroundCapacity to deliver intravenous Alzheimer's disease (AD) treatments could constitute an obstacle to access in addition to AD specialist and PET scan capacity.ObjectiveWe aim to estimate the overall capacity for AD treatment infusions compared to expected demand in the United States.MethodsWe used published data and a survey of infusion sites to estimate the capacity to deliver AD treatments in physician offices, hospitals, standalone centers and at patients' homes from 2024 to 2033 relative to demand.ResultsCapacity for intravenous AD treatments is predicted to increase from 370,000 in 2024 to 5.2 million infusions in 2033. Nevertheless, a significant shortfall of over 13 million infusions remains in 2033, which would imply delayed access for 2.2 million patients.ConclusionsLimited infusion capacity could impede AD treatment access and result in avoidable disability progression. Expansion of capacity is needed in the short run until treatments with alternative routes of administration become available.},
}

@article {pmid40877951,
year = {2025},
author = {Jiao, HS and Ge, YJ and Huang, LY and Liu, Y and Wu, BS and Lian, PP and Hao, YN and Han, SS and Li, YT and Wu, KM and Wu, CY and Cheng, TL and Yuan, P and Yu, JT},
title = {MS4A6A/Ms4a6d deficiency disrupts neuroprotective microglia functions and promotes inflammation in Alzheimer's disease model.},
journal = {Molecular neurodegeneration},
volume = {20},
number = {1},
pages = {94},
pmid = {40877951},
issn = {1750-1326},
support = {82071201//National Natural Science Foundation of China/ ; 32371036//National Natural Science Foundation of China/ ; 2022ZD0211600//Science and Technology Innovation 2030 Major Projects/ ; 2023SHZDZX02//Shanghai Municipal Science and Technology Major Project/ ; 2022JC01//Shanghai Municipal Health Commission Emerging Interdisciplinary Research Project/ ; 22TQ019//Shanghai Pilot Program for Basic Research - FuDan University 21TQ1400100/ ; LG-QS-202203-09//Lingang Laboratory/ ; },
mesh = {*Alzheimer Disease/genetics/metabolism/pathology ; *Microglia/metabolism/pathology ; Humans ; Animals ; Mice ; Genome-Wide Association Study ; Disease Models, Animal ; *Inflammation/metabolism/genetics/pathology ; Male ; Female ; Mice, Transgenic ; Neuroprotection/physiology ; Membrane Proteins ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is the most common type of dementia. Genetic polymorphisms are associated with altered risks of AD onset, pointing to biological processes and potential targets for interventions. Consistent with the important roles of microglia in AD development, genetic mutations of several genes expressed on microglia have been identified as risks for AD. Emerging evidences indicate that the expression of a microglia-specific gene MS4A6A is thought to be associated with AD, since AD patients show upregulation of MS4A6A, and its levels correlate with the severity of clinical neuropathology. However, the mechanism linking MS4A6A and AD has not been experimentally studied.

METHODS: We performed a meta genome-wide association analysis with 734,121 subjects to examine the associations between polymorphisms of MS4A6A with AD risks. In addition, we analyzed the correlation between MS4A6A and AD-related cerebrospinal fluid biomarkers from our own cohort. Furthermore, we for the first time generated a Ms4a6d deficient APP/PS1 model, and systematically examined pathological changes using high-resolution microscopy, biochemistry, and behavioral analysis.

RESULTS: We identified several new mutations of MS4A6A with altered AD risks, and discovered specific correlation for some of them with the amount of β-amyloid in cerebrospinal fluid. Protective variant of MS4A6A is associated with elevated expression of the gene. Deficient Ms4a6d led to reduced amyloid clearance in the brain. Immunostaining from postmortem AD patients brain revealed selective expression of MS4A6A in microglia. In APP/PS1 mice lacking Ms4a6d, microglia showed markedly diminished envelopment and phagocytosis of amyloid, leading to increased plaque burden, less compact structure, and more severe synaptic damage. Importantly, Ms4a6d deficiency markedly exacerbated inflammatory responses in both microglia and astrocytes by disinhibiting NF-κB signaling. Overexpressing MS4A6A in human microglia cell line promoted gene expression related to plaque-associated responses and diminished inflammation signatures.

CONCLUSIONS: Our findings reveal that Ms4a6d deficiency suppresses neuroprotection and worsens neuroinflammation. Sufficient Ms4a6d maybe beneficial for boosting amyloid-related responses and suppressing inflammation in microglia, making it superior than previously reported candidates for microglia modulation. Thus, the elevated MS4A6A levels in AD are likely compensatory and boosting MS4A6A could be an effective treatment.},
}

*Alzheimer Disease/genetics/metabolism/pathology
*Microglia/metabolism/pathology
Humans
Animals
Mice
Genome-Wide Association Study
Disease Models, Animal
*Inflammation/metabolism/genetics/pathology
Male
Female
Mice, Transgenic
Neuroprotection/physiology
Membrane Proteins

@article {pmid40877781,
year = {2025},
author = {Poulet, PE and Tran, M and Tezenas du Montcel, S and Dubois, B and Durrleman, S and Jedynak, B and , },
title = {Prediction-powered inference for clinical trials: application to linear covariate adjustment.},
journal = {BMC medical research methodology},
volume = {25},
number = {1},
pages = {204},
pmid = {40877781},
issn = {1471-2288},
abstract = {Prediction-powered inference (PPI) (Angelopoulos et al., Science 382(6671):669-674, 2023) and its subsequent development called PPI++ (Angelopoulos et al., 2023) provide a novel approach to standard statistical estimation, leveraging machine learning systems, to enhance unlabeled data with predictions. We use this paradigm in clinical trials. The predictions are provided by disease progression models, providing prognostic scores for all the participants as a function of baseline covariates. The proposed method would empower clinical trials by providing untreated digital twins of the treated patients while remaining statistically valid. The potential implications of this new estimator of the treatment effect in a two-arm randomized clinical trial (RCT) are manifold. First, it leads to an overall reduction of the sample size required to reach the same power as a standard RCT. Secondly, it advocates for an imbalance of controls and treated patients, requiring fewer controls to achieve the same power. Finally, this technique directly transfers any disease prediction model trained on large cohorts to practical and scientifically valid use. In this paper, we demonstrate the theoretical properties of this estimator and illustrate them through simulations. We show that it is asymptotically unbiased for the Average Treatment Effect and derive an explicit formula for its variance. We then compare this estimator to a regression-based linear covariate adjustment method. An application to an Alzheimer's disease clinical trial showcases the potential to reduce the sample size.},
}

@article {pmid40877780,
year = {2025},
author = {Brosch, JR and Summanwar, D and Fowler, NR and Hammers, DB and Perkins, AJ and Higbie, A and Swartzell, K and Willis, DR},
title = {An innovative health systems approach to support early detection of cognitive impairment in primary care - the brain health navigator.},
journal = {BMC primary care},
volume = {26},
number = {1},
pages = {271},
pmid = {40877780},
issn = {2731-4553},
abstract = {BACKGROUND: Patients and providers experience barriers to early detection of mild cognitive impairment (MCI) and dementia. We developed a new primary care-based role, the Brain Health Navigator (BHN), who is trained to assess patients for cognitive impairment, identify addressable causes, suggest appropriate diagnostic testing, connect patients to resources, and assist patients in accessing disease-modifying treatments and dementia care management. This study describes the BHN role, the feasibility of implementing the BHN in Primary Care (PC) clinics, and the initial patients' outcomes for those who saw the BHN.

METHODS: Patients ≥65 years were screened with a Digital Cognitive Assessment (DCA) in seven PC clinics from June 1, 2022, to May 31, 2023. Patients who scored likely cognitively impaired or borderline for impairment were eligible for referral to the BHN. Clinics and providers could determine if referrals were automatic or on a patient-by-patient basis. The BHN encounter included a comprehensive assessment of standardized tools and suggested laboratory and imaging studies to facilitate the diagnostic process and connect patients to resources, care and treatment, and research opportunities.

RESULTS: 466 of 861 patients with likely impaired or borderline impaired DCA results were referred to the BHN.More patients with likely impaired scores (62.7%) were referred to the BHN compared to those with borderline scores (47.6%). Of the 466 referred patients, 28.9% with likely impaired scores and 23.5% with borderline scores completed a BHN visit. Patients who were seen by the BHN had a significantly higher likelihood of receiving a new diagnosis of MCI than patients who did not see the BHN and were more likely to have orders for diagnostic tests, such as vitamin B12 thyroid function and Magnetic Resonance Imaging of the head and neck. Referrals to both neurology and neuropsychology were significantly more common among patients who completed the BHN visit.

CONCLUSIONS: A BHN enhances follow-up care and monitoring for patients with abnormal cognitive screening tests. A BHN visit increases the rate of evidence-based diagnostic evaluation for MCI and dementia in PC.

TRIAL REGISTRATION: This study was designated as exempt by the Indiana University Institutional Review Board (#15281).},
}

@article {pmid40877101,
year = {2025},
author = {Lahmar, T and Thuau, F and Pinard, G and Boutoleau-Bretonniere, C and Perrot, P and Lancien, U},
title = {Brain lymphatic drainage pathways, deep cervical lymphatic surgery, and current insights: A systematic review.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {},
number = {},
pages = {100335},
doi = {10.1016/j.tjpad.2025.100335},
pmid = {40877101},
issn = {2426-0266},
abstract = {The discovery of the glymphatic system and the later rediscovery of the meningeal lymphatic network have significantly changed our understanding of central nervous system (CNS) waste clearance. Aging is linked to a gradual decline in these clearance pathways, resulting in waste buildup. As a result, therapeutic strategies targeting cerebral lymphatic function have garnered growing interest, with lymphatic surgery emerging as a promising option. We conducted a review until July 2025, providing an overview of the potential of lymphatic surgical techniques to enhance CNS metabolic waste clearance pathways as a therapeutic approach for brain lymphatic system disorders. Currently available data are limited, nine publications addressing this approach. These studies explore an innovative technique involving lymphatico-venous anastomoses (LVA) targeting deep cervical lymphatic vessels to promote clearance for the treatment of Alzheimer's or Parkinson's diseases. Cerebral lymphatic drainage is critical for effective brain waste elimination such as amyloid-β, phosphorylated tau, and α-synuclein, which are linked to neurodegenerative diseases. Viewing these lymphatic dysfunctions as a form of "cerebral lymphedema," LVA, already used in treating peripheral lymphedema, shows potential as a therapeutic approach. Although clinical evidence is still limited, lymphatic supermicrosurgery presents promising therapeutic possibilities for neurodegenerative diseases and other conditions related to impaired CNS lymphatic outflow.},
}

@article {pmid40874776,
year = {2025},
author = {Chen, Y and Dong, C and Chen, J and Li, Q},
title = {Clinical observations on treating Alzheimer's disease with umbilical cord blood mononuclear cells.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251366669},
doi = {10.1177/13872877251366669},
pmid = {40874776},
issn = {1875-8908},
abstract = {BackgroundThere are currently no relevant clinical research reports on the application of human umbilical cord blood mononuclear cells (hUCBMCs) treatment for Alzheimer's disease (AD) in humans.ObjectiveTo observe the clinical efficacy of intravenous transplantation of hUCBMCs in patients with AD.MethodsEleven AD patients with Clinical Dementia Rating (CDR) scores of 1 (mild) or 2 (moderate) were selected. Patients continued standard AD medication and received three intravenous infusions of UCBMCs, spaced seven days apart. Neurological and psychological assessments, including MMSE, ADAS-Cog, ADL, and PSQI scores, were conducted by neurologists at baseline and 1, 3, and 6 months post-treatment. The impact of UCBMCs on cognitive function, daily living activities, sleep disorders, and any adverse reactions were monitored. Repeated measures ANOVA and LSD-t post-hoc tests were used to analyze score changes.ResultsRepeated measures ANOVA revealed differences in MMSE, ADAS-Cog, ADL, and PSQI scores across the evaluated time points. Pairwise comparisons indicated substantial improvements, with MMSE scores increasing at 1, 3, and 6 months post-treatment, while ADAS-Cog scores decreased. ADL scores showed improvement at 1 and 3 months, and PSQI scores decreased consistently at all post-treatment intervals. Notably, MMSE and ADL scores peaked at 3 months before gradually declining, ADAS-Cog scores reached their lowest point at 3 months before increasing, and PSQI scores were lowest at 1 month, followed by a gradual rise.ConclusionsIntravenous infusion of UCBMCs can temporarily improve cognitive function, enhance daily living activities, and alleviate sleep disorders in AD patients, with a high safety profile.},
}

@article {pmid40873665,
year = {2025},
author = {Parks, AL and Thacker, A and Dohan, D and Gomez, LAR and Gale, SA and Johnson, KG and Ritchie, CS and Shah, SJ and Paladino, J},
title = {Characterizing clinician communication with patients about lecanemab: A qualitative study of clinicians across seven academic medical centers.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {11},
number = {3},
pages = {e70150},
pmid = {40873665},
issn = {2352-8737},
abstract = {INTRODUCTION: Anti-amyloid monoclonal antibodies (mAbs) slow cognitive decline in Alzheimer's disease but may cause amyloid-related imaging abnormalities (ARIA), which can rarely be disabling or fatal. This qualitative study investigates how clinicians communicate the benefits and risks of mAbs to patients and caregivers.

METHODS: Semi-structured interviews with clinicians who prescribe mAbs at seven academic medical centers. Hybrid inductive-deductive thematic analysis by interdisciplinary researchers.

RESULTS: In 27 clinician interviews (women [n = 17], White individuals [n = 19], neurologists [n = 17]), three themes emerged. First, clinicians varied in techniques used and concepts emphasized, including using analogies, discussing statistics, and emphasizing versus de-emphasizing risks. Second, patient contextual factors (e.g., comorbidities), hopes, and fears shaped communication. Third, clinician communication varied by training, personal style, and ambivalence. While clinicians honor patients' choices to pursue treatment, many do not "recommend" it (but may recommend against it).

DISCUSSION: Preliminary insights about how clinicians communicate tradeoffs can guide future shared decision-making interventions for mAbs.

HIGHLIGHTS: This qualitative study among 27 clinicians across seven academic medical centers examined how clinicians communicate with people with Alzheimer's disease about risks and benefits of anti-amyloid therapy, which can influence treatment decisions.Clinicians varied in what techniques they employed and how they portrayed risks and benefits, and whether they incorporated patients' values.They cited comorbidities, eligibility criteria fit, and degree of social support or family involvement in decisions as factors used in framing discussions, while fewer used patients' goals to guide discussion.The professional training, individual practice style, and personal sense of ambivalence of clinicians shaped conversations.These findings can guide future interventions to improve communication and shared decision-making.},
}

@article {pmid40873639,
year = {2025},
author = {Huang, G and Liu, Y and Zhu, X and He, L and Chen, T},
title = {Exploring the Neuroprotective Role of Selenium: Implications and Perspectives for Central Nervous System Disorders.},
journal = {Exploration (Beijing, China)},
volume = {5},
number = {4},
pages = {e20240415},
pmid = {40873639},
issn = {2766-2098},
abstract = {Selenium (Se) is a crucial element in selenoproteins, key biomolecules for physiological function in vivo. As a selenium-rich organ, the central nervous system can express all 25 kinds of selenoproteins, which protect neurons by reducing oxidative stress and inflammatory response. However, decreased Se levels are prevalent in a variety of neurological disorders, which is not conducive to the treatment and prognosis of patients. Thus, the biological study of Se has emerged as a focal point in investigating the pivotal role of trace elements in neuroprotection. This paper presents a comprehensive review of the pathogenic mechanism of neurological diseases, the protective mechanism of Se, and the neurological protective function of selenoproteins. Additionally, the application of Se as a neuroprotective agent in neurological disorder therapy, including ischemic stroke, Alzheimer's, Parkinson's, and other neurological diseases, is summarized. The present review aims to offer novel insights and methodologies for the prevention and treatment of neurological disorders with trace Se, providing a scientific basis for the development of innovative Se-based neuroprotectants to promote their clinical application against neurological diseases.},
}

@article {pmid40872731,
year = {2025},
author = {Vitturini, C and Cerquetella, M and Spaterna, A and Bazzano, M and Marchegiani, A},
title = {Diagnosis of Canine Cognitive Dysfunction Syndrome: A Narrative Review.},
journal = {Veterinary sciences},
volume = {12},
number = {8},
pages = {},
doi = {10.3390/vetsci12080781},
pmid = {40872731},
issn = {2306-7381},
abstract = {Many recent progresses in the overall quality of life have allowed for an increase in life expectancy, both in humans and in dogs. In addition, long-lived individuals may develop neurodegenerative disorders, and one of the most important in human medicine is Alzheimer's disease (AD). In veterinary medicine, the AD counterpart is Canine Cognitive Dysfunction Syndrome (CCDS), which, generally, affects elderly dogs from 8 years of age. These cognitive disorders are becoming frequently encountered conditions and, despite researchers' attention towards pathogenesis, treatment and diagnosis, more efforts are required to outline which clinical and laboratory evaluations must be carried out to reach a presumptive antemortem diagnosis of CCDS. The biggest need is the establishment of standardized protocols and guidelines for a correct clinical and diagnostic approach towards dogs with clinical signs referrable to CCDS. In this narrative review, we examined the up-to-date scientific literature on the topic, focusing our attention on sensitive and reliable markers for clinical antemortem CCDS diagnosis. Even if some parameters analyzed are interesting and promising, more investigations are needed to confirm the results obtained so far. This is crucial because a correct diagnosis is fundamental to determine the best treatment and, thus, to guarantee animals' health and welfare.},
}