@article {pmid41202483,
year = {2025},
author = {Yuan, C and Li, L and Lin, HY and Aubry, AV and Parise, LF and Morel, C and Chen, F and Wong, J and Russo, SJ and Wang, J},
title = {Targeting neuronal activity and neuroinflammation for the treatment of Alzheimer's disease in a mouse model.},
journal = {Neurobiology of aging},
volume = {157},
number = {},
pages = {111-118},
doi = {10.1016/j.neurobiolaging.2025.10.006},
pmid = {41202483},
issn = {1558-1497},
abstract = {Alzheimer's disease (AD) is characterized by progressive cognitive decline driven by complex pathological processes, including tau hyperphosphorylation (p-Tau), amyloid-beta (Aβ) accumulation, and neuroinflammation. In this study, we investigated the effects of two bioactive compounds, dihydrocaffeic acid (DHCA) and malvidin-glucoside (Mal-gluc), targeting inflammation and neuronal activity, respectively, on cognitive function and AD pathology in a mouse model of AD. Our results demonstrate that chronic DHCA/Mal-gluc treatment significantly improves recognition memory in 3xTg-AD mice without reducing p-Tau or Aβ burden. Employing a newly developed whole-brain cFOS and IBA-1 mapping technique, we found that this combination treatment enhances neuronal activity and promotes microglial homeostasis across multiple brain regions in 3xTg-AD mice. These findings underscore the potential of restoring neuronal function and immune homeostasis as a therapeutic approach for AD. Future study will explore the underlying mechanisms and evaluate whether DHCA/Mal-gluc, combined with currently approved Aβ monoclonal therapy, can synergistically prevent or delay AD onset and progression.},
}

@article {pmid41202479,
year = {2025},
author = {Samsami, S and Parvar, MD and Mehralitabar, H and Dehghanbanadaki, N and Naderi-Manesh, H},
title = {In silico investigation of CNS-11 as a potential inhibitor of Aβ42 aggregation and its protofibril disassembly.},
journal = {Biochemical and biophysical research communications},
volume = {790},
number = {},
pages = {152899},
doi = {10.1016/j.bbrc.2025.152899},
pmid = {41202479},
issn = {1090-2104},
abstract = {Amyloidogenic peptide aggregation and fibril formation are key components in neurodegenerative diseases such as Alzheimer's disease (AD). One effective strategy for treating these conditions involves preventing amyloid peptide aggregation by using interfering agents, such as small molecules, at the onset of amyloid peptide assembly. Another approach could involve destabilizing the formed fibrils using small molecules as well. In this study, we utilized both all-atom and coarse-grained molecular dynamics (MD) simulation methods to investigate the aggregation mechanistic details of amyloid-β42 (Aβ42) peptides, the impact of CNS-11 (a small molecule inhibitor with proven Tau fibrils decomposing agent) on this Aβ42 aggregation, and the destabilization effect of CNS-11 on an Aβ42 fiber section, alongside the Aβ42 fiber section itself. Our results demonstrated that Aβ42 monomers in the free state strongly tend to dimerize and form beta-sheets by integrating the hydrophobic sections of the Aβ42 peptides. Still, as CNS-11 was added to the system, the ligand formed a hydrophobic core composed of CNS-11 and Aβ42 peptides surrounding this core, resulting in an amorphous and significantly disordered structure. Additionally, CNS-11 could interact with the Aβ42 pre-formed fiber section, partially destabilizing it through interactions with the buried hydrophobic core. Moreover, simulating the Aβ42 fiber section revealed that the N-terminal region of these peptide aggregates is naturally flexible and capable of becoming disorganized even without the addition of external disrupting agents. This study provides comprehensive insights into the molecular-level mechanisms underlying the dual effects of CNS-11 on amyloid beta aggregation and fibril degradation. This study can provide a computational framework with the potential to be applied to various small molecules, exploring their potential in the prevention and treatment of Alzheimer's disease.},
}

@article {pmid41201547,
year = {2025},
author = {Akkaya, EC and Ilgin, R and Adil, H and Çelik, A},
title = {Magnesium L-Threonate Reduces Hippocampal Amyloid-β Load without Cognitive Improvement in a PTU-induced Hypothyroidism Model in Young Rats.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {8},
pmid = {41201547},
issn = {1559-1182},
support = {TSA-2024-565//Usak University Research Foundation/ ; },
mesh = {Animals ; *Hippocampus/metabolism/drug effects/pathology ; *Amyloid beta-Peptides/metabolism ; *Hypothyroidism/chemically induced/drug therapy/metabolism ; *Cognition/drug effects ; Disease Models, Animal ; Male ; Rats ; Rats, Wistar ; Brain-Derived Neurotrophic Factor/metabolism ; Maze Learning/drug effects ; },
abstract = {The brain is among the most critical target organs for thyroid hormones. Therefore, both congenital and acquired hypothyroidism can have significant neuropsychiatric consequences. Learning and memory problems, concentration disorders, and some psychiatric disorders such as depression can be observed in diseases causing acquired hypothyroidism. Although thyroid hormone therapy is the standard treatment, it does not always fully reverse these neuropsychiatric complications. Several studies have demonstrated the positive effects of magnesium L-threonate (MgT) supplementation on cognitive functions. Research suggests that MgT may help alleviate cognitive deficits, particularly in neurodegenerative conditions like Alzheimer's disease, where it has been associated with improvements in memory and reductions in hippocampal amyloid-β accumulation. However, there is limited data on the effect of MgT supplementation on hypothyroid conditions in the brain. The purpose of this study was to evaluate the effects of MgT supplementation on cognitive functions in hypothyroid rats. We report that while MgT supplementation did not significantly improve cognitive performance in behavioral tasks or inflammatory markers in hypothyroid rats, it did increase hippocampal BDNF levels in euthyroid animals and reduced hippocampal amyloid-β load under both euthyroid and hypothyroid conditions. The reduction in amyloid beta load under hypothyroid conditions suggests that MgT may exert partial therapeutic effects even in the absence of thyroid hormone replacement. These findings highlight the need for further studies to evaluate the therapeutic potential of MgT, particularly in combination with thyroid hormone replacement.},
}

Animals
*Hippocampus/metabolism/drug effects/pathology
*Amyloid beta-Peptides/metabolism
*Hypothyroidism/chemically induced/drug therapy/metabolism
*Cognition/drug effects
Disease Models, Animal
Male
Rats
Rats, Wistar
Brain-Derived Neurotrophic Factor/metabolism
Maze Learning/drug effects

@article {pmid41200978,
year = {2025},
author = {Zhang, Y and Fan, J and Nan, S and Pan, J and Guo, W and Zhang, Y},
title = {Rubiadin Alleviates Alzheimer's Disease Pathology via NF-κB Pathway Regulation.},
journal = {Journal of integrative neuroscience},
volume = {24},
number = {10},
pages = {33497},
doi = {10.31083/JIN33497},
pmid = {41200978},
issn = {0219-6352},
support = {20210101293JC//Natural Science Foundation of Jilin Province/ ; },
mesh = {Animals ; *Alzheimer Disease/drug therapy/metabolism/pathology ; Mice ; *NF-kappa B/metabolism/drug effects ; Disease Models, Animal ; *Neuroprotective Agents/pharmacology/administration & dosage ; *Signal Transduction/drug effects ; Mice, Transgenic ; Male ; Amyloid beta-Peptides/metabolism ; Plaque, Amyloid/metabolism/drug therapy ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is a severe neurodegenerative disorder that impacts the global impact on the population. Nevertheless, the intricate nature of its pathogenesis has posed significant challenges to drug discovery in this field. This study aimed to verify the therapeutic potential of rubiadin (RB) on AD through both in vivo and in vitro experiments, thereby facilitating translational research for the advancement of AD treatment.

METHODS: We investigated the neuroprotective effects of RB on AD using both in vivo and in vitro models. Immunohistochemistry and western blot analysis were employed to evaluate inflammatory factors and the Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway in Mo/HuAPP695swe (APP)/PS1-dE9 (PS1) mice and N2a cells.

RESULTS: RB enhanced the memory performance of APP/PS1 mice in various tests, including the Morris water maze, step-down and step-through passive avoidance tasks, and novel object recognition. RB reduced the accumulation of Amyloid-beta (Aβ) plaques, as shown by immunohistochemical analysis. It also decreased the expression levels of pro-inflammatory cytokines interleukin (IL)-1β, IL-6, and tumor necrosis factor-alpha (TNF-α), while increasing the release of IL-4. Additionally, RB inhibited the NF-κB pathway, as demonstrated by western blot. Moreover, a cell viability test showed that RB protected N2a cells against toxicity caused by Aβ1-42 through a cell viability test. Western blot analysis revealed that neuroinflammation and the NF-κB pathway were inhibited by RB treatment in Aβ1-42-induced N2a cells. Accordingly, RB suppressed the nuclear translocation of NF-κB in Aβ1-42-induced N2a cells.

CONCLUSIONS: Our results provide experimental evidence supporting the preclinical research and future clinical applications of RB, thereby facilitating the development of new drugs for AD clinical therapy.},
}

Animals
*Alzheimer Disease/drug therapy/metabolism/pathology
Mice
*NF-kappa B/metabolism/drug effects
Disease Models, Animal
*Neuroprotective Agents/pharmacology/administration & dosage
*Signal Transduction/drug effects
Mice, Transgenic
Male
Amyloid beta-Peptides/metabolism
Plaque, Amyloid/metabolism/drug therapy

@article {pmid41200903,
year = {2025},
author = {Chockchowwat, W and Hannongbua, S and Saparpakorn, P},
title = {Role of triterpenoid derivatives from Centella asiatica as quantum chemical calculations.},
journal = {Journal of biomolecular structure & dynamics},
volume = {},
number = {},
pages = {1-17},
doi = {10.1080/07391102.2025.2578225},
pmid = {41200903},
issn = {1538-0254},
abstract = {To date, the treatment for Alzheimer's disease (AD) has focused on the cholinergic hypothesis, particularly through the inhibition of acetylcholinesterase (AChE). Asiatic acid, madecassic acid, asiaticoside, and madecassoside, which are triterpenoid derivatives from Centella asiatica, have previously been reported to exhibit the AChE inhibitory activity. This study aimed to investigate their binding modes and to determine efficient computational methods for analyzing their interactions with AChE. Molecular dynamics simulations demonstrated that most of their equilibrated structures remained within the AChE binding site. Principal component analysis and free energy landscape (FEL) confirmed their stability of the binding. Among the evaluated methods, the MM-(ALPB)SA binding energies, when combined with ligand surface binding efficiency index, showed the best correlation with experimental binding free energy. Density functional theory (DFT) calculations revealed the common key interaction between triterpenoids and AChE, including hydrogen bonds (Tyr124, Arg296, Tyr337, and Tyr341), H-π (Tyr341) and van der Waals (Trp86) interactions. Additionally, pharmacokinetics and drug-likeness predictions indicated that madecassic acid and asiatic acid are promising candidates for drug development. This study highlights the potential of triterpenoid derivatives in AChE inhibition and provides valuable insights into their binding efficiency, which could contribute to future drug discovery targeting Alzheimer's disease.},
}

@article {pmid41200863,
year = {2025},
author = {Wang, C and Shao, X and Cao, X and Fan, T and Li, Z and Wang, K and Li, M and Wang, X and Guan, P and Hu, X},
title = {Silver-functionalized carbon dots regulate amyloid aggregation and microbial infection.},
journal = {Nanoscale},
volume = {},
number = {},
pages = {},
doi = {10.1039/d5nr03379a},
pmid = {41200863},
issn = {2040-3372},
abstract = {Amyloid accumulation and microbial infections are major risk factors for Alzheimer's disease (AD). However, most of the current drugs are limited to single-target therapeutic strategies against amyloid or microbial infections, resulting in poor clinical treatment effects. Herein, we propose a novel multi-targeted strategy that can achieve multiple effects of inhibition of amyloid aggregation, depolymerization of mature amyloid fibrils, and anti-microbial infection. Experiments conducted in vitro have shown that silver-functionalized carbon dots (Ag@TACDs), at concentrations as low as 10 μg mL[-1], significantly impact the misfolding of Aβ42 and the depolymerization of Aβ42 fibrils. Moreover, Ag@TACDs exhibit outstanding ability to resist bacterial infections. At the same time, Ag@TACDs have good biocompatibility, enhance cell activity, and alleviate the cytotoxicity caused by Aβ42 oligomers. Our approach provides an effective strategy for the design of multi-target inhibitors for Alzheimer's disease.},
}

@article {pmid41199875,
year = {2025},
author = {Chande, K and Nirmal, R and Varpe, N and Doke, R and Vinchurkar, K and Singh, S},
title = {Alkaloid's undiscovered neuroprotective potential: a multi-target strategy to fight against neurodegenerative illnesses.},
journal = {3 Biotech},
volume = {15},
number = {12},
pages = {409},
pmid = {41199875},
issn = {2190-572X},
abstract = {Neurodegeneration (ND) refers to the progressive decline of neurons, leading to Alzheimer's disease, Parkinson's disease, multiple sclerosis, and Huntington's disease. These conditions are marked by gradual neuronal loss and cognitive impairment, with limited treatment options currently available. The available strategies only provide symptomatic relief and having more side effects, however none of them able to halt the disease progression, so there is strong need to develop alternative therapeutic strategies with no or less toxicity. Alkaloids, a class of naturally occurring compounds, exhibit diverse biological activities, including antioxidant and neuroprotection. Emerging research suggests that these molecules can influence key signaling pathways associated with neurodegeneration, potentially offering therapeutic benefits. By targeting multiple aspects of disease progression and modulating neuroinflammatory responses, alkaloids interact with critical molecular components such as transcription factors, receptors, and enzymes essential for neuronal survival and homeostasis. This review underscores the therapeutic potential of alkaloids in ND treatment and emphasizes the need for further research to explore their clinical applications. Future studies should aim to identify neuroprotective alkaloids, elucidate their mechanisms of action, and assess their effectiveness in treating neurodegenerative diseases. A deeper understanding of their interactions with key disease pathways is crucial for the development of effective therapeutic strategies.},
}

@article {pmid41199470,
year = {2025},
author = {Shao, Y and Liu, L and Zhu, S and Zhu, Z and Wang, P and Biswal, BB and Lin, H},
title = {Fornix Mediates Information Propagation in Brain Networks Following DLPFC-Targeted rTMS in Alzheimer's Disease: A Randomized Controlled Trial.},
journal = {CNS neuroscience & therapeutics},
volume = {31},
number = {11},
pages = {e70630},
doi = {10.1111/cns.70630},
pmid = {41199470},
issn = {1755-5949},
support = {CFH2022-2-2014//Capital's Funds for Health Improvement and Research/ ; 2022YFC2402205//National Key R&D Program of China/ ; 51977205//National Natural Science Foundation of China/ ; NSFC62401106//National Natural Science Foundation of China/ ; NSFC62171101//National Natural Science Foundation of China/ ; NSFC-AF 82211530041//NSFC Projects of International Cooperation and Exchanges/ ; 2024NSFSC1661//Sichuan Science and Technology Program/ ; },
mesh = {Humans ; *Alzheimer Disease/therapy/diagnostic imaging/physiopathology ; Male ; Female ; *Transcranial Magnetic Stimulation/methods ; Aged ; *Fornix, Brain/diagnostic imaging/physiopathology/physiology ; *Dorsolateral Prefrontal Cortex/diagnostic imaging/physiopathology/physiology ; Diffusion Tensor Imaging ; Middle Aged ; *Nerve Net/diagnostic imaging/physiopathology ; White Matter ; Aged, 80 and over ; Neural Pathways ; },
abstract = {AIMS: Repetitive transcranial magnetic stimulation (rTMS) could improve the clinical manifestations in Alzheimer's disease (AD), but its impact on deep brain tissue related to memory remains unclear. This study explored whether rTMS targeting cortical gray matter could regulate the white matter (WM) and exert modulatory effects on the network through WM bundles.

METHODS: Seventy-three AD patients underwent 14-day rTMS over the left dorsolateral prefrontal cortex (44 real, 25 sham). Granger causality analysis assessed changes in effective connectivity (EC) between the fornix and whole-brain voxels. Furthermore, the effects of rTMS treatment on fiber tracking parameters were analyzed.

RESULTS: After rTMS therapy, patients with AD showed increased EC based on fornix in the real-stimulation group. Functional network projections indicated that these clusters belonged to the frontoparietal network, the somatomotor network, as well as three white matter networks. Additionally, increased EC associated with fornix exhibited lateralization on the right side. Diffusion tensor imaging results showed no significant differences after the 14-day rTMS treatment.

CONCLUSION: In conclusion, a 14-day rTMS treatment in AD could regulate fornical function by increasing cortical-fornix EC, indicating neuroplasticity changes in response to therapy.

TRIAL REGISTRATION: Chinese Clinical Trial Registry (https://www.chictr.org.cn/index.html; ChiCTR2200062564).},
}

Humans
*Alzheimer Disease/therapy/diagnostic imaging/physiopathology
Male
Female
*Transcranial Magnetic Stimulation/methods
Aged
*Fornix, Brain/diagnostic imaging/physiopathology/physiology
*Dorsolateral Prefrontal Cortex/diagnostic imaging/physiopathology/physiology
Diffusion Tensor Imaging
Middle Aged
*Nerve Net/diagnostic imaging/physiopathology
White Matter
Aged, 80 and over
Neural Pathways

@article {pmid41198610,
year = {2025},
author = {Pirraglia, E and Osorio, RS and Glodzik, L and Ashebir, Y and Shao, Y},
title = {Subtypes of multiple-etiology dementias and the heterogeneous impact of APOE variants.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {11},
pages = {e70872},
doi = {10.1002/alz.70872},
pmid = {41198610},
issn = {1552-5279},
support = {U01OH012486//Centers for Disease Control and Prevention (CDC)/ ; U24 AG072122/NH/NIH HHS/United States ; R01NS104364/NH/NIH HHS/United States ; R01HL111724/NH/NIH HHS/United States ; P01 AG060882/AG/NIA NIH HHS/United States ; P30 AG066512/AG/NIA NIH HHS/United States ; P30AG062429/AG/NIA NIH HHS/United States ; P30AG066468/AG/NIA NIH HHS/United States ; P30AG062421/AG/NIA NIH HHS/United States ; P30AG066509/AG/NIA NIH HHS/United States ; P30AG066514/AG/NIA NIH HHS/United States ; P30AG066530/AG/NIA NIH HHS/United States ; P30AG066507/AG/NIA NIH HHS/United States ; P30AG066444/AG/NIA NIH HHS/United States ; P30AG066518/AG/NIA NIH HHS/United States ; P30AG066462/AG/NIA NIH HHS/United States ; P30AG072979/AG/NIA NIH HHS/United States ; P30AG072972/AG/NIA NIH HHS/United States ; P30AG072976/AG/NIA NIH HHS/United States ; P30AG072975/AG/NIA NIH HHS/United States ; P30AG072978/AG/NIA NIH HHS/United States ; P30AG072977/AG/NIA NIH HHS/United States ; P30AG066519/AG/NIA NIH HHS/United States ; P30AG062677/AG/NIA NIH HHS/United States ; P30AG079280/AG/NIA NIH HHS/United States ; P30AG062422/AG/NIA NIH HHS/United States ; P30AG066511/AG/NIA NIH HHS/United States ; P30AG072946/AG/NIA NIH HHS/United States ; P30AG062715/AG/NIA NIH HHS/United States ; P30AG072973/AG/NIA NIH HHS/United States ; P30AG066506/AG/NIA NIH HHS/United States ; P30AG066508/AG/NIA NIH HHS/United States ; P30AG066515/AG/NIA NIH HHS/United States ; P30AG072947/AG/NIA NIH HHS/United States ; P30AG072931/AG/NIA NIH HHS/United States ; P30AG066546/AG/NIA NIH HHS/United States ; P20AG068024/AG/NIA NIH HHS/United States ; P20AG068053/AG/NIA NIH HHS/United States ; P20AG068077/AG/NIA NIH HHS/United States ; P20AG068082/AG/NIA NIH HHS/United States ; P30AG072958/AG/NIA NIH HHS/United States ; P30AG072959/AG/NIA NIH HHS/United States ; R01AG056031/AG/NIA NIH HHS/United States ; R01AG056531/AG/NIA NIH HHS/United States ; R01AG067523/AG/NIA NIH HHS/United States ; R01AG066870/AG/NIA NIH HHS/United States ; R21AG067549/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; Male ; Female ; *Dementia/genetics/mortality/pathology/classification ; *Apolipoproteins E/genetics ; *Alzheimer Disease/pathology/genetics/mortality ; Aged ; Aged, 80 and over ; Autopsy ; *Apolipoprotein E4/genetics ; Brain/pathology ; Mixed Dementias ; },
abstract = {INTRODUCTION: Multiple-etiology dementias (MEDs) are frequently identified at autopsy but often missed in clinical diagnosis, limiting the efficiency of dementia research and treatment. This study aimed to characterize subtypes of MEDs, evaluate clinical underdiagnosis, and assess the heterogeneous impact of apolipoprotein E (APOE) variants on mortality across MED subtypes.

METHODS: Data from the National Alzheimer's Coordinating Center (NACC) repository, which includes standardized clinical and autopsy assessments, were analyzed using competing risks survival models.

RESULTS: Pure Alzheimer's disease (AD) neuropathology was rare, whereas mixed neuropathologies were common and frequently misdiagnosed as AD alone. APOE ε4 decreased mortality risk in decedents without AD neuropathology and increased mortality in decedents with mixed AD neuropathology, but not in those with AD alone. APOE ε2 increased mortality in decedents having vascular neuropathology with cerebral amyloid angiopathy.

DISCUSSION: Heterogeneity in MEDs remains substantially underrecognized clinically. The effects of APOE variants vary by dementia subtype, emphasizing the need for refined diagnostic tools and personalized dementia treatment and care approaches.

HIGHLIGHTS: Autopsy data revealed that pure Alzheimer's disease (AD) neuropathology is rare, whereas mixed pathologies are highly prevalent and frequently misdiagnosed as AD alone in clinical settings, underscoring the limitations of current diagnostic practices. Comprehensive neuropathological characterization of multiple-etiology dementia (MED) subtypes is crucial for uncovering the true complexity of dementia, which is often masked in clinical assessments. This approach enables a more accurate understanding of disease mechanisms and progression. We found that apolipoprotein E (APOE) ε4 was associated with increased mortality risk in AD with co-pathologies, but not in pure AD without other neuropathologies. Conversely, APOE ε4 was associated with decreased mortality risk in decedents who did not have AD neuropathology. APOE ε2 was protective in some AD-related subtypes but was associated with higher mortality risk in cerebral amyloid angiopathy with other vascular neuropathologies, highlighting the heterogeneous impact of genetic risk factors across subtypes. The differential effects of APOE variants across MED subtypes emphasize the need to evaluate biomarkers and risk factors within the context of underlying neuropathological profiles rather than broad clinical categories. These findings reinforce the need to develop and implement more refined, subtype-specific biomarkers and diagnostic protocols to enable precision prevention and personalized treatment strategies for the diverse forms of MED.},
}

Humans
Male
Female
*Dementia/genetics/mortality/pathology/classification
*Apolipoproteins E/genetics
*Alzheimer Disease/pathology/genetics/mortality
Aged
Aged, 80 and over
Autopsy
*Apolipoprotein E4/genetics
Brain/pathology
Mixed Dementias

@article {pmid41198603,
year = {2025},
author = {Crowley, P and Henry, AL and Flanagan, E and Antonsdottir, I and Bentley, A and Blackman, J and Bliwise, DL and Bubu, OM and Buysse, DJ and Camargos, EF and Cassidy-Eagle, E and Cote, K and Coulthard, E and D'Rozario, AL and Espie, CA and Falck, RS and Gabb, VG and Harvey, AG and Hmwe, NTT and Hoyos, CM and Jobbins, L and Kennelly, S and Kent, BA and Köpke, S and Krystal, A and Leroi, I and Liguori, C and Lim, YY and Lorenz, R and Lucey, BP and Mander, B and Moline, M and Naismith, SL and Ogunniyi, A and Rapaport, P and Reynolds, CF and Richards, K and Siengsukon, CF and Sindi, S and Singer, CM and Wirz-Justice, A and Yaffe, K and O'Caoimh, R},
title = {Development of a core outcome set for clinical trials of interventions to improve sleep in people with cognitive impairment-the Sleep in Cognitive Impairment Core Outcome Set (SCICOS).},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {11},
pages = {e70890},
doi = {10.1002/alz.70890},
pmid = {41198603},
issn = {1552-5279},
support = {HRB DTICTN-2021-003//Dementia Trials Ireland, Health Research Board Clinical Trial Network/ ; HRB DTICTN-2021-003/HRBI_/Health Research Board/Ireland ; },
mesh = {Humans ; *Cognitive Dysfunction/complications/therapy ; *Sleep Wake Disorders/therapy/etiology/complications ; *Clinical Trials as Topic ; *Outcome Assessment, Health Care ; Delphi Technique ; *Sleep ; },
abstract = {INTRODUCTION: Sleep disturbances are common in older people with cognitive impairment, potentially contributing to negative outcomes. A core outcome set (COS) is required to reduce heterogeneity in clinical trials and promote the development of high-quality evidence to support clinical management.

METHODS: A multi-stage mixed methods study was conducted in accordance with The Core Outcome Set Standards for Development.

RESULTS: A systematic review identified 287 sleep outcomes from previous clinical trials. Qualitative interviews ensured the COS was informed by what matters most to people with cognitive impairment and their caregivers. A modified Delphi process identified nine outcomes for the COS: total sleep time, sleep onset latency, wakefulness after sleep onset, number of night-time awakenings, sleep efficiency, and measures of sleep quality, daytime sleepiness, cognition, and mood.

DISCUSSION: This COS will support researchers to produce more reliable and coherent trial data to guide the management of sleep disturbances in people with neurodegenerative cognitive impairment.

HIGHLIGHTS: Evidence is lacking regarding the treatment of sleep disturbances in people with cognitive impairment. Heterogeneity of reported outcomes in clinical trials limits data synthesis. A qualitative analysis established what matters most to people with cognitive impairment and their caregivers when determining treatment effectiveness. A Delphi panel of experts agreed upon a core outcome set. This core outcome set will improve the reliability and comparability of data from future trials.},
}

Humans
*Cognitive Dysfunction/complications/therapy
*Sleep Wake Disorders/therapy/etiology/complications
*Clinical Trials as Topic
*Outcome Assessment, Health Care
Delphi Technique
*Sleep

@article {pmid41198506,
year = {2025},
author = {Lafon, PA and Prézeau, L and Pin, JP and Rondard, P},
title = {Nanobodies: a new paradigm for brain disorder therapies.},
journal = {Trends in pharmacological sciences},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.tips.2025.10.004},
pmid = {41198506},
issn = {1873-3735},
abstract = {Camelid-derived nanobodies offer a promising alternative to conventional antibodies for the treatment of brain disorders. Their current development in models of schizophrenia or Alzheimer's disease highlights their strong therapeutic potential. Optimizing their delivery and ensuring their safety are major challenges, but their modularity and low immunogenicity make them promising candidates for neurotherapy.},
}

@article {pmid41198224,
year = {2025},
author = {Yadav, D and Knight-Greenfield, A and Moirano, J and Nordvig, A and Salgado, MW and Hamed, M and Lin, M and RoyChoudhury, A and Blum, S and Keil, SA and Intorcia, B and Ebani, EJ and Osborne, J and Chiang, G and Ivanidze, J},
title = {Amyloid PET Z-score Quantification and correlation with visual semiquantitative grading.},
journal = {AJNR. American journal of neuroradiology},
volume = {},
number = {},
pages = {},
doi = {10.3174/ajnr.A9079},
pmid = {41198224},
issn = {1936-959X},
abstract = {BACKGROUND AND PURPOSE: Amyloid PET imaging plays a crucial role in the diagnosis of Alzheimer's disease (AD) and determines eligibility for anti-amyloid therapies. While visual interpretation using Regional Cortical Tracer Uptake (RCTU) and Brain Amyloid Plaque Load (BAPL) scores remains standard in clinical practice, it is subject to inter-reader variability and may not fully depict the amyloid distribution pattern. RCTU scoring evaluates cortical tracer uptake quantified as 1: no uptake, 2: focal and 3: diffuse uptake, while BAPL provides an overall summary score of amyloid plaque load depending on highest RCTU score. Quantitative techniques such as Centiloid scale or Z-scores may assist in diagnosis, grading and treatment monitoring. This study evaluates the feasibility of a Z-score quantification generated from normative database comparison and its correlation with visual RCTU grading.

MATERIALS AND METHODS: We retrospectively analyzed 100 patients who underwent [F18]-Florbetaben PET imaging between August and October 2024 for cognitive impairment. Visual interpretation was performed using RCTU scoring and overall BAPL score. Quantitative Z-scores were calculated for four cortical regions (frontal, parietal, posterior cingulate/precuneus, and lateral temporal) using a normative database. Correlation between visual and quantitative scores was assessed using Spearman's correlation. Z-score differences among RCTU categories were evaluated with Kruskal Wallis and Mann Whitney tests.

RESULTS: Among 100 patients (median age 78), 31 were amyloid negative (BAPL1), and 69 were amyloid positive (11 BAPL2, and 58 BAPL3). A total of 400 cortical regions were evaluated (143 RCTU1, 46 RCTU2, 211 RCTU3). Strong positive correlations were observed between RCTU and Z-scores in all regions (ρ = 0.78-0.88, p < 0.0001). The regional Z-scores showed significant differences between RCTU1 and RCTU2, RCTU1 and RCTU3, as well as between RCTU2 and RCTU3 across all four regions (p<0.05 for all comparisons. Pooled regional analysis also showed statistically significant differences in Z-scores between all RCTU groups (p < 0.0001).

CONCLUSIONS: Quantitative regional Z-scores derived from amyloid PET imaging demonstrate a strong correlation with visual assessment (RCTU score), validating their feasibility in clinical interpretation. These findings support the integration of quantitative tools into routine practice to enhance diagnostic confidence, reduce reader variability, and monitoring for amyloid-targeted therapies.

ABBREVIATIONS: AD = Alzheimer's Disease; RCTU = Regional Cortical Tracer Uptake; BAPL = Brain Amyloid Plaque Load; PiB = Pittsburgh Compound B; SUVR = Standardized Uptake Value Ratio; SPM = Statistical Parametric Mapping; SSP = Stereotactic Surface Projections.},
}

@article {pmid41197936,
year = {2025},
author = {Choi, H and Hwang, SB and Cho, HY and Ahn, S and Yun, HY and Song, JS},
title = {Memantine modulates neuroinflammation and motor coordination in a Parkinson's disease model.},
journal = {Brain research},
volume = {},
number = {},
pages = {150034},
doi = {10.1016/j.brainres.2025.150034},
pmid = {41197936},
issn = {1872-6240},
abstract = {Memantine, an NMDA receptor antagonist clinically approved for Alzheimer's disease, has been implicated in modulating neuroinflammatory responses beyond its anti-excitotoxic actions. To explore its potential relevance in Parkinson's disease, this study evaluated memantine's effects in both LPS-activated microglial cells and a synucleinopathy mouse model. In BV-2 cells, memantine elicited a modest but measurable attenuation of TNF-α and IL-6 secretion, which was accompanied by downregulation of TLR4 and IκB signaling. In vivo, 5-month oral administration of memantine to mThy1-αSyn transgenic mice led to moderate improvements in motor function as assessed by beam-walk performance. Immunohistochemical analyses revealed decreased microglial activation in the cerebral cortex; however, phosphorylated α-synuclein accumulation and tyrosine hydroxylase expression remained unaffected. Furthermore, spatial working memory was not improved by treatment. Taken together, these findings suggest that memantine may exert beneficial effects on neuroinflammatory processes and behavioral deficits in PD-relevant models. However, its impact on the hallmark neuropathology of PD appears limited.},
}

@article {pmid41197760,
year = {2025},
author = {Yao, M and Li, Z and Lin, Y and Cai, H and Sun, C and Liu, L and Long, Y and Ge, Z},
title = {Hyperbaric oxygen therapy ameliorates Alzheimer's disease pathology by restoration of mitophagy and suppressing neuroinflammation in 5xFAD mice.},
journal = {Experimental neurology},
volume = {},
number = {},
pages = {115534},
doi = {10.1016/j.expneurol.2025.115534},
pmid = {41197760},
issn = {1090-2430},
abstract = {Alzheimer's disease (AD) is characterized by amyloid-β (Aβ) accumulation, synaptic dysfunction, and chronic neuroinflammation. Here, we demonstrate that hyperbaric oxygen therapy (HBOT) has multiple therapeutic effects in 5xFAD transgenic mice. HBOT significantly improved cognitive function. Treated mice increasingly moved to the center of the open field in Y-maze tests and preferred a new arm. Longitudinal [18]F-AV-45 PET-MR scans showed progressive reduction in amyloid tracer uptake, which was corroborated by histologically verified reduced plaque burden and upregulation of LRP1, a key Aβ clearance transporter. HBOT preserved neuronal density and enhanced synaptic proteins. Mechanistically, HBOT promoted mitochondrial quality control by upregulating PINK1 and parkin expression, enhancing autophagosome formation, and modulating mitophagy-associated pathways. The transition of microglia to a surveillance phenotype was reflected in decreased soma area and increased branching. The coordinated improvement in amyloid clearance, mitochondrial quality control and synaptic maintenance, and modulation of neuroinflammation suggest that the ability of HBOT to simultaneously act on multiple pathological cascades-in combination with its noninvasive nature and favorable safety profile-makes it a uniquely promising therapeutic strategy. Furthermore, these results suggest that HBOT may be particularly effective at an early stage of the disease. These studies will be critical in establishing the clinical applicability of HBOT in the treatment of Alzheimer's disease.},
}

@article {pmid41197747,
year = {2025},
author = {Ozturk, B and Demir, H and Silindir-Gunay, M and Akdag, Y and Sahin, S and Gulsun, T},
title = {Application of Artificial Neural Network to Determine Optimum Formulation Development and In Vitro Characterization of Methylene Blue and Galantamine Loaded Polymeric Nanoparticles for the Treatment of Alzheimer's Disease.},
journal = {European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences},
volume = {},
number = {},
pages = {107364},
doi = {10.1016/j.ejps.2025.107364},
pmid = {41197747},
issn = {1879-0720},
abstract = {Alzheimer's disease is a major neurodegenerative disorder characterized by complex pathophysiology and currently lacks a curative treatment. This study aims to develop and characterize methylene blue and galantamine co-loaded PLGA nanoparticles, surface-modified with poloxamer 188 and GSH, to increase blood residence time and improve brain-targeted delivery. The nanoparticles were prepared using the double emulsion solvent evaporation method, and their physicochemical properties were characterized by TEM, FT-IR, DSC, XRD, and [13]C NMR. Artificial neural network modeling was used to optimize the formulation parameters, including PLGA %, PVA %, and sonication time, for predicting particle size and encapsulation efficiencies of methylene blue and galantamine. Results showed that the optimized nanoparticles had particle sizes less than 200 nm, appropriate zeta potential, and high encapsulation efficiencies. DSC, FT-IR, XRD, and NMR analyses confirmed the absence of crystalline peaks for methylene blue and galantamine, indicating successful encapsulation. Artificial neural network models demonstrated high predictive accuracy, serving as a valuable tool for formulation optimization. This dual-drug, surface-modified nanoparticle approach offers promising potential for multi-target therapy in Alzheimer's disease.},
}

@article {pmid41196512,
year = {2025},
author = {Li, Y and Fan, H and Han, X and Ni, M and Hou, X and Xia, H and Shi, Y and Zhang, L and Sun, J},
title = {RRBP1 Inhibition Reduces Microglial M1 Polarization and Inflammation-Mediated Neuronal Loss and Oxidative Stress by Regulating ERK Pathway in Alzheimer's Disease.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {5},
pmid = {41196512},
issn = {1559-1182},
support = {No. ZC23456043 and No. ZC2020259//The 23456 Talent Project of Henan Provincial People's Hospital/ ; },
mesh = {*Oxidative Stress/drug effects/physiology ; *Microglia/metabolism/pathology/drug effects ; *Alzheimer Disease/pathology/metabolism ; Animals ; Humans ; *Neurons/metabolism/pathology/drug effects ; *Inflammation/pathology/metabolism ; *MAP Kinase Signaling System/drug effects/physiology ; Mice ; *Cell Polarity/drug effects ; Cell Line ; Reactive Oxygen Species/metabolism ; Amyloid beta-Peptides ; Cell Line, Tumor ; Apoptosis/drug effects ; },
abstract = {Ribosome-binding protein 1 (RRBP1) regulates ribosome assembly and stability to modify several important biological processes such as mitochondrial function, stress, cell differentiation, immunity, and axonal structure. This study aimed to investigate RRBP1 inhibition on microglial polarization and inflammation, and its mediated neuronal loss and oxidative stress in Alzheimer's disease (AD). Mouse microglia (BV-2), mouse hippocampal neuron (HT-22), human microglia (HMC3), and human neuroblastoma (SH-SY5Y) cell lines were cultured. A classical culture system containing BV-2 and HT-22, as well as HMC3 and SH-SY5Y, under β-amyloid treatment was applied to mimic AD cellular models. RRBP1 siRNA and control siRNA were transfected into BV-2 and HMC3 cells with no transfection as normal control; moreover, the ERK pathway was inactivated by PD98059 reagent. Microglial M1 phonotype marker (iNOS) and inflammatory cytokines (TNF-α and IL-1β levels) were decreased, while microglial M2 phonotype marker (ARG1) and pERK/ERK were increased by RRBP1 inhibition in BV-2 and HMC3 cells. Then microglial RRBP1 inhibition further elevated cell viability and superoxide dismutase (SOD), while reducing the cell apoptosis rate and reactive oxygen species (ROS) in HT-22 and SH-SY5Y cells. pERK/ERK was lowered after PD98059 treatment, which attenuated the effect of RRBP1 inhibition on microglial M1/M2 phenotypes and inflammatory cytokines in BV-2 and HMC3 cells, and further weakened the effect of microglial RRBP1 inhibition on cell viability, apoptosis rate, ROS, and SOD in HT-22 and SH-SY5Y cells. RRBP1 inhibition represses microglial M1 polarization and inflammation-mediated neuronal loss and oxidative stress by modifying the ERK pathway in AD.},
}

*Oxidative Stress/drug effects/physiology
*Microglia/metabolism/pathology/drug effects
*Alzheimer Disease/pathology/metabolism
Animals
Humans
*Neurons/metabolism/pathology/drug effects
*Inflammation/pathology/metabolism
*MAP Kinase Signaling System/drug effects/physiology
Mice
*Cell Polarity/drug effects
Cell Line
Reactive Oxygen Species/metabolism
Amyloid beta-Peptides
Cell Line, Tumor
Apoptosis/drug effects

@article {pmid41196470,
year = {2025},
author = {Vaja, R and Vohra, M and Ramachandran, AV and Baxi, D},
title = {Development of a Novel Aluminium Chloride-Induced Zebrafish Model of Alzheimer's Disease: Involvement of Oxidative Stress, Cholinergic Dysfunction, and Gut Pathophysiology.},
journal = {Neurotoxicity research},
volume = {43},
number = {6},
pages = {46},
pmid = {41196470},
issn = {1476-3524},
mesh = {Animals ; Zebrafish ; *Oxidative Stress/drug effects/physiology ; *Alzheimer Disease/chemically induced/physiopathology/pathology/metabolism ; *Disease Models, Animal ; Female ; Male ; *Aluminum Chloride/toxicity ; Brain/pathology/drug effects/metabolism ; },
abstract = {Alzheimer's Disease (AD) is a progressive and fatal neurodegenerative disorder (NDD), and the leading cause of dementia globally, with females being more susceptible than males. Existing animal models for AD are primarily pharmacologically induced or transgenic, yet many fail to recapitulate the full spectrum of human AD pathology and thereby elucidating its sex-based differences. This underscores the need for a cost-effective and robust experimental model that reliably mimics the multifactorial nature of AD taking into account the differences that arise due to sex. In recent years, the zebrafish (Danio rerio) has emerged as a promising model organism for studying central nervous system (CNS) disorders, including AD, owing to its high genetic and physiological homology to humans, transparent embryonic development, and amenability to high-throughput screening. This study aims to establish a novel chronic neurotoxicity induced ZF model, using AlCl3 as an inducing neurotoxic agent. The hypothesis centers on AlCl3-induced oxidative stress, cholinergic pathway dysfunction, and gut pathophysiological changes as drivers of AD-like pathology. Adult zebrafish, of both sexes were exposed to chronic AlCl3 treatment over a 28-day period. Post-treatment assessments included histopathological, biochemical, and behavioural analyses to evaluate changes in brain and gut tissues, oxidative stress biomarkers, and cognitive performance. Zebrafish exposed to AlCl3 exhibited distinct pathological changes in both brain and gut tissues compared to controls. In the brain, hallmarks such as pyknotic neurons, neuronal vacuolisation, and neural tissue necrosis was observed. Gut tissue displayed significant abnormalities, including reduced villi number, epithelial cell loss, and fused or shortened villi. Biochemical analyses revealed elevated oxidative stress, evidenced by altered levels of catalase (CAT), glutathione (GSH), and lipid peroxidation (LPO). Additionally, disruption of the cholinergic system was evident. Behavioural analyses using locomotor tracking revealed marked cognitive deficits, including reduced average speed, decreased distance travelled, and increased immobility. Lastly, our sex specific differences revealed that females were more affected by the biochemical, histological and neurobehavioural parameters as compared to males, thereby indicating that females pose a greater susceptibility towards developing AD. The AlCl3 -induced zebrafish model successfully replicates key features of human neurotoxicity, which may lead to AD like features including oxidative stress, cholinergic dysfunction, neurodegeneration, and gut-brain axis alterations. This novel and cost-effective model provides a comprehensive platform for exploring sex-mediated neurotoxicity experimental animal model and offers potential utility for screening therapeutic interventions and understanding disease-modifying mechanisms. Keywords: Alzheimer's Disease, Chronic Neurotoxicity, Gut-brain axis, Zebrafish, Sex differences, Alumnium chloride.},
}

Animals
Zebrafish
*Oxidative Stress/drug effects/physiology
*Alzheimer Disease/chemically induced/physiopathology/pathology/metabolism
*Disease Models, Animal
Female
Male
*Aluminum Chloride/toxicity
Brain/pathology/drug effects/metabolism

@article {pmid41196440,
year = {2025},
author = {Li, S and Gao, Y and Zhang, X and Lang, J and Liu, X and Zhang, Y and Zhang, J and Zhao, Y and Chang, C and Gao, X and Zhou, J and Yu, D and Yang, G},
title = {Bicyclol improves cognition deficits and inhibits oxidative stress-induced neuronal cell apoptosis in alzheimer's disease via Nrf2/HO-1 pathway.},
journal = {Metabolic brain disease},
volume = {40},
number = {8},
pages = {310},
pmid = {41196440},
issn = {1573-7365},
support = {Grant No. 20220997//the Medical Science Research Project of Hebei Provincial Health Commission/ ; Grant No. 82471453//the National Natural Science Foundation of China/ ; Grant No. H2022206231//the Hebei Natural Science Foundation/ ; },
mesh = {Animals ; *Apoptosis/drug effects ; *NF-E2-Related Factor 2/metabolism ; *Oxidative Stress/drug effects ; *Alzheimer Disease/drug therapy/metabolism ; *Biphenyl Compounds/pharmacology/therapeutic use ; Mice ; *Neurons/drug effects/metabolism ; *Heme Oxygenase-1/metabolism ; *Cognitive Dysfunction/drug therapy/metabolism ; Neuroprotective Agents/pharmacology/therapeutic use ; Signal Transduction/drug effects ; Male ; Mice, Transgenic ; Disease Models, Animal ; Antioxidants/pharmacology ; Amyloid beta-Peptides ; Membrane Proteins ; },
abstract = {Alzheimer's disease (AD) is identified as the prevalent neurodegenerative condition globally, ultimately resulting in dementia. Currently, the mechanisms that contribute to AD are not well comprehended, and there are few therapeutic alternatives available. Bicyclol, a substance extracted from the Chinese herb Schisandra Chinensis, has shown remarkable antioxidant, anti-inflammatory, anti-apoptotic, and neuroprotective characteristics. However, there is a shortage of research focusing on the therapeutic effects of bicyclol on AD as well as the molecular pathways that may be involved. This study sought to evaluate the effects of bicyclol on cognitive impairments in a mouse model of AD, explore its neuroprotective benefits associated with antioxidant functions and apoptosis suppression, and reveal the mechanisms involved. In this study, APP/PS1 mice underwent a 2-month treatment with bicyclol administered via gavage, after which their cognitive abilities were evaluated through behavioral assessments. The apoptosis of cortical neurons was evaluated using TUNEL staining and immunofluorescence techniques. N2A cells, which were exposed to Aβ1-42 oligomers, received a pretreatment with bicyclol, and their viability was subsequently measured. The expression levels of proteins such as nuclear factor E2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), NAD(P) H-quinine oxidoreductase-1 (NQO1), BCL2 associated X Protein (Bax), B-cell lymphoma-2 (Bcl-2), and Cleaved caspase-3 were quantified in vitro and in vivo using western blotting and qPCR methods. Moreover, N2A cells lacking Nrf2 were utilized to investigate the underlying mechanisms through which bicyclol exerts its effects in Alzheimer's disease. Bicyclol has been shown to enhance cognitive function while simultaneously reducing the levels of cortical Aβ1-40 and Aβ1-42, and it also protects against neuronal degeneration in the APP/PS1 mouse model. Moreover, it increases the activity of cortical SOD and GSH-Px, concurrently decreasing levels of ROS and MDA in vivo. Additionally, bicyclol significantly lessened oxidative stress and apoptosis induced by Aβ1-42 in N2A cells. It further elevated the expression of proteins such as Nrf2, HO-1, and NQO1, along with mRNA levels in both in vitro and in vivo experiments. Furthermore, the silencing of Nrf2 via siRNA transfection counteracted the regulatory effects of bicyclol on apoptotic markers including Bax, Bcl-2, and Cleaved caspase-3 in vitro. Our study provides compelling evidence that bicyclol effectively alleviates cognitive impairments observed in APP/PS1 mice. Furthermore, our findings indicate that bicyclol plays a significant role in reducing oxidative stress-induced injury and neuronal apoptosis. This protective effect is associated with the activation of the Nrf2/HO-1 signaling pathway. These results suggest that bicyclol has the potential to be developed as a therapeutic agent for the treatment of Alzheimer's disease, highlighting its promise in addressing the cognitive decline associated with this debilitating condition.},
}

Animals
*Apoptosis/drug effects
*NF-E2-Related Factor 2/metabolism
*Oxidative Stress/drug effects
*Alzheimer Disease/drug therapy/metabolism
*Biphenyl Compounds/pharmacology/therapeutic use
Mice
*Neurons/drug effects/metabolism
*Heme Oxygenase-1/metabolism
*Cognitive Dysfunction/drug therapy/metabolism
Neuroprotective Agents/pharmacology/therapeutic use
Signal Transduction/drug effects
Male
Mice, Transgenic
Disease Models, Animal
Antioxidants/pharmacology
Amyloid beta-Peptides
Membrane Proteins

@article {pmid41196439,
year = {2025},
author = {Yadav, P and Dabas, A and Singh, R},
title = {Six-membered N-heterocyclic alkaloids as ChE inhibitors in alzheimer's disease treatment.},
journal = {Metabolic brain disease},
volume = {40},
number = {8},
pages = {309},
pmid = {41196439},
issn = {1573-7365},
mesh = {*Alzheimer Disease/drug therapy/enzymology ; *Cholinesterase Inhibitors/therapeutic use/pharmacology ; Humans ; *Alkaloids/therapeutic use/pharmacology/chemistry ; Animals ; Butyrylcholinesterase/metabolism ; Acetylcholinesterase/metabolism ; *Heterocyclic Compounds/therapeutic use/pharmacology ; },
abstract = {Cholinesterase (ChE) refers to a group of enzymes that play a critical role in the hydrolysis of choline-based esters, particularly acetylcholine, a key neurotransmitter presents in the nervous system. The two types of cholinesterase are acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), each with distinct functions and locations found within the body. Cholinesterase inhibitors (ChEIs) have been utilized to treat Alzheimer's disease (AD). AD is a progressive neurodegenerative disorder characterized by memory loss, impacting on the quality of life. Many studies have highlighted the potential of alkaloids as inhibitors of cholinesterase enzymes. There are various alkaloids which have potential to treat AD with their different modes of actions. This review summarizes more than 14 well-known alkaloids possessing six-membered N-heterocycles as AChE and BuChE inhibitors, such as berberine, boldine, crytolepine, harmine, huperzine A, 6-hydroxycrinamine, nicotine, piperine, salsoline, skimmianine, trigonelline, valerianofal A, 7'-multijuguinone, and 12'-hydroxy-7'-multijuguinone, hamayne, and lycorine.},
}

*Alzheimer Disease/drug therapy/enzymology
*Cholinesterase Inhibitors/therapeutic use/pharmacology
Humans
*Alkaloids/therapeutic use/pharmacology/chemistry
Animals
Butyrylcholinesterase/metabolism
Acetylcholinesterase/metabolism
*Heterocyclic Compounds/therapeutic use/pharmacology

@article {pmid41195067,
year = {2025},
author = {Ye, K and Li, L and Guan, L and Qin, MM and Xu, XY and Wu, J and Huang, LZ and Gao, JJ},
title = {Exploring the molecular mechanisms of Pueraria in Alzheimer's disease treatment using machine learning and network pharmacology.},
journal = {Frontiers in nutrition},
volume = {12},
number = {},
pages = {1683852},
pmid = {41195067},
issn = {2296-861X},
abstract = {BACKGROUND: Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder, characterized by amyloid-β deposition, tau pathology, neuroinflammation, and metabolic dysfunction. While conventional treatments have been widely studied, food-based interventions are emerging as potential neuroprotective strategies. Pueraria, a nutrient-rich food, has shown promise in promoting brain health, but its mechanisms in AD prevention and management remain insufficiently understood.

METHODS: In this study, we utilized network pharmacology, transcriptomics, and machine learning to investigate the neuroprotective effects of Pueraria. Through analysis of five transcriptomic datasets (GSE5281, GSE29378, GSE36980, GSE37263, and GSE138260), we identified genes associated with AD and screened 15 active compounds from Pueraria lobata using HERB and TCMSP databases. Machine learning models prioritized key targets, and molecular docking simulations assessed the binding affinities of Pueraria compounds to these targets. In vivo validation was performed in AD model mice to evaluate the cognitive-enhancing effects of Pueraria.

RESULTS: We identified 45 overlapping targets between Pueraria and AD, primarily related to synaptic plasticity and neurotransmission. Among these, PFKFB3 emerged as a key mediator of Pueraria's neuroprotective effects. Molecular docking confirmed strong binding affinities between Pueraria compounds and PFKFB3, supporting their functional role. Experimental data showed that Pueraria improved cognitive function in AD mice, underscoring its potential as a neuroprotective agent.

CONCLUSION: This study highlights Pueraria as a promising functional food for AD prevention and management, emphasizing the potential of plant-based dietary interventions for brain health. Our findings provide a basis for further exploration of food-derived neuroprotective strategies.},
}

@article {pmid41193962,
year = {2025},
author = {Jahani, S and Roshanaei, G and Tapak, L and , },
title = {Assessing the accuracy of survival machine learning and traditional statistical models for Alzheimer's disease prediction over time: a study on the ADNI cohort.},
journal = {BMC medical research methodology},
volume = {25},
number = {1},
pages = {250},
pmid = {41193962},
issn = {1471-2288},
mesh = {Humans ; *Alzheimer Disease/diagnosis/diagnostic imaging ; *Machine Learning ; Male ; Female ; Aged ; *Cognitive Dysfunction/diagnosis/diagnostic imaging ; Disease Progression ; *Models, Statistical ; Aged, 80 and over ; Neuroimaging/methods ; Prognosis ; Cohort Studies ; Proportional Hazards Models ; Survival Analysis ; },
abstract = {BACKGROUND: Mild cognitive impairment (MCI) represents a transitional stage to Alzheimer's disease (AD), making progression prediction crucial for timely intervention. Predictive models integrating clinical, laboratory, and survival data can enhance early diagnosis and treatment decisions. While machine learning approaches effectively handle censored data, their application in MCI-to-AD progression prediction remains limited, with unclear superiority over classical survival models.

METHODS: We analyzed 902 MCI individuals from Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset with 61 baseline features. Traditional survival models (Cox proportional hazards, Weibull, elastic net Cox) were compared with machine learning techniques (gradient boosting survival, random survival forests [RSF]) for progression prediction. Models were evaluated using C-index and IBS.

RESULTS: Following feature selection, 14 key features were retained for model training. RSF achieved superior predictive performance with the highest C-index (0.878, 95% CI: 0.877-0.879) and lowest IBS (0.115, 95% CI: 0.114-0.116), demonstrating statistically significant superiority over all evaluated models (P-value < 0.001). RSF demonstrated effective risk stratification across individual biomarker categories (genetic, imaging, cognitive) and achieved optimal patient separation into three distinct prognostic groups when combining all features (p < 0.0001). SHAP-based feature importance analysis of RSF revealed cognitive assessments as the most influential predictors, with Functional Activities Questionnaire (FAQ) achieving the highest importance score (1.098), followed by Logical Memory Delayed Recall Total (LDELTOTAL) (0.906) and Alzheimer's Disease Assessment Scale (ADAS13) (0.770). Among neuroimaging biomarkers, Fluorodeoxyglucose (FDG) emerged as the leading predictor (0.634), ranking fifth overall. Feature importance ranking differed between classical and machine learning approaches, with FDG maintaining consistent importance across all models. RSF demonstrated excellent predictive calibration with positive net benefit across risk thresholds from 0.2 to 0.8.

CONCLUSIONS: The RSF model outperformed other methods, demonstrating superior potential for improving prognostic accuracy in medical diagnostics for MCI to AD progression.},
}

Humans
*Alzheimer Disease/diagnosis/diagnostic imaging
*Machine Learning
Male
Female
Aged
*Cognitive Dysfunction/diagnosis/diagnostic imaging
Disease Progression
*Models, Statistical
Aged, 80 and over
Neuroimaging/methods
Prognosis
Cohort Studies
Proportional Hazards Models
Survival Analysis

@article {pmid41193931,
year = {2025},
author = {Nagarajan, R and Zhang, H and Lyu, J and Kambali, M and Wang, M and Rudolph, U},
title = {Intranasal Insulin Mitigates Memory Impairment and Neuroinflammation in a Mouse Model of Hippocampal Aging.},
journal = {Pharmacology research & perspectives},
volume = {13},
number = {6},
pages = {e70186},
pmid = {41193931},
issn = {2052-1707},
support = {R01GM128183/GM/NIGMS NIH HHS/United States ; R35GM153232/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Administration, Intranasal ; *Insulin/administration & dosage/pharmacology ; Mice ; *Memory Disorders/drug therapy ; Disease Models, Animal ; *Hippocampus/drug effects/metabolism ; *Aging/drug effects ; *Neuroinflammatory Diseases/drug therapy ; Male ; Somatostatin/metabolism ; Mice, Inbred C57BL ; Mice, Transgenic ; },
abstract = {Aging is a complex process that frequently includes cognitive decline with memory loss. In the hippocampus, the number of somatostatin-positive (Sst[+]) GABAergic interneurons in the hilar region of the dentate gyrus decreases with age. We previously showed that selective ablation of Sst[+] dentate hilar interneurons is sufficient to induce cognitive dysfunction, resulting in a model of hippocampal aging (pseudo-aged mice). Brain insulin levels and insulin receptor expression also decline with age, and intranasal insulin (INS) has shown promise in improving learning and memory in Alzheimer's disease. Here, we investigated the effects of INS in pseudo-aged mice with genetically ablated dentate hilar Sst[+] interneurons, which were generated by bilateral injection of AAV5-EF1α-mCherry-flex-dtA into the dentate hilus of Sst-IRES-Cre mice (3-5 months old). Following a 3-week recovery period post-injection, INS was administered daily for 9 days. INS treatment in pseudo-aged mice improved working memory in the Y-maze, recognition memory in the novel object recognition test, and non-declarative associative memory in trace fear conditioning. At the molecular level, INS reversed the increase in Iba-1 and pTBK1 expression, indicating attenuation of microglial activation and cGAS-STING pathway signaling, and restored hippocampal BDNF levels. No significant effects of INS were observed in control mice. These findings indicate that INS alleviates memory impairment and reduces neuroinflammation in this hippocampal aging model. Together, the results suggest that intranasal insulin may provide a non-invasive therapeutic approach for mitigating age-related cognitive decline by modulating neuroinflammatory and neurotrophic mechanisms.},
}

Animals
Administration, Intranasal
*Insulin/administration & dosage/pharmacology
Mice
*Memory Disorders/drug therapy
Disease Models, Animal
*Hippocampus/drug effects/metabolism
*Aging/drug effects
*Neuroinflammatory Diseases/drug therapy
Male
Somatostatin/metabolism
Mice, Inbred C57BL
Mice, Transgenic

@article {pmid41192715,
year = {2025},
author = {Wang, J and Du, Z and Wang, W and Liang, Z and Hou, Y and Liu, Q and Wang, J and Wang, S and He, M and Li, Z and Yang, R and Wang, K and Zhao, L and Wei, Y and Huang, D},
title = {Lactoferrin-driven delivery of Kaixinsan nanomedicine for Alzheimer's disease neuroprotection: Mechanistic insights from bioinformatics and multi-target validation.},
journal = {International journal of biological macromolecules},
volume = {},
number = {},
pages = {148746},
doi = {10.1016/j.ijbiomac.2025.148746},
pmid = {41192715},
issn = {1879-0003},
abstract = {Alzheimer's disease (AD) is a common neurodegenerative disorder characterised by neurapoptosis and neuroinflammation-induced neuronal damage. However, the exact pathogenic mechanism of AD is still controversial, and the existing treatment methods are only effective for the early stage of the disease. Kaixinsan (KXS), a classic anti-amnestic traditional Chinese medicine, can effectively reduce oxidative stress and provide neuroprotection to the brain, but the exact molecular mechanism remains unclear. Herein, we synthesised a biomimetic KXS-delivery system (LTF@GO-PEG/KXS, LGPK), which significantly enhanced the blood-brain barrier (BBB) penetration efficiency was significantly improved, attributed to lactoferrin (LTF)-mediated receptor binding. LGPK exhibits excellent neuroprotection and repolarizes BV2 microglia from pro-inflammatory to anti-inflammatory phenotypes. Further bioinformatics analysis and western blot results indicated that LGPK could inhibit the progression of AD by inhibiting the production of amyloid precursor protein (APP) and hyperphosphorylated Tau (p-Tau), and downregulating TNF/NF-κB signalling pathways. In vivo studies using a transgenic Caenorhabditis elegans strain confirmed that LGPK both suppresses Aβ fibrillogenesis and attenuates oxidative stress, thereby highlighting its potential as a combination therapy for AD. Mechanistic investigations indicated that these neuroprotective effects were mediated through the suppression of the TNF/NF-κB signalling pathway, along with profound alterations in alternative splicing (AS) events. Collectively, these findings highlight LGPK as a promising multi-target nanomedicine for AD treatment by enhancing brain-targeted delivery and exerting combined anti-neuroapoptosis and anti-inflammatory.},
}

@article {pmid40490537,
year = {2025},
author = {Frontzkowski, L and Gnörich, J and Gross, M and Dehsarvi, A and Roemer-Cassiano, SN and Palleis, C and Katzdobler, S and Dewenter, A and Steward, A and Biel, D and Hirsch, F and Zhu, Z and Levin, J and Stephens, AW and Müller, A and Koglin, N and Bischof, GN and Kovacs, GG and Höglinger, GU and Brendel, M and Franzmeier, N},
title = {Developing a novel reference region for [[18]F]PI-2620-PET imaging to facilitate the assessment of 4-repeat tauopathies.},
journal = {European journal of nuclear medicine and molecular imaging},
volume = {52},
number = {13},
pages = {5098-5112},
pmid = {40490537},
issn = {1619-7089},
abstract = {PURPOSE: Progressive supranuclear palsy (PSP) is a fatal 4-repeat (4R) tauopathy with progressive movement phenotypes. In-vivo 4R tau biomarkers are therefore crucial for PSP diagnosis, monitoring, and treatment evaluation. The tau-PET tracer [[18]F]PI-2620 binds to 4R tau and shows increased uptake in PSP-associated regions (e.g., globus pallidus), and is therefore a candidate 4R tau biomarker. However, commonly used cerebellar tau-PET reference regions show regional proximity to cerebellar 4R tau deposits in PSP, confounding semiquantitative [[18]F]PI-2620 assessments. Therefore, we employed bias-free image-derived input function (IDIF) PET quantification to identify an optimized data-driven reference region for assessing 4R tau in PSP.

METHODS: Dynamic [[18]F]PI-2620 PET (60 min) was acquired in 58 PSP-Richardson Syndrome (PSP-RS) and 18 healthy controls (HC). IDIF-modelling with carotid timeseries derived total distribution volume (VT). Iteratively normalizing VT images to atlas-based white matter (WM), we identified reference candidates maximizing PSP-RS vs. HC pallidum differences. The best-performing WM references were combined to a temporo-orbital WM reference, validated in PSP-nonRS (n = 54), HC (n = 18), and disease controls (α-synucleinopathies, n = 21; Alzheimer’s disease (AD, n = 22) using VT-ratios (VTr) and 20-40min static standardized uptake value ratios (SUVr).

RESULTS: Using the data-driven temporo-orbital WM reference, PSP patients showed significantly higher basal ganglia [[18]F]PI-2620 signal vs. HC compared to cerebellar normalization. Receiver operating curve (ROC) analysis confirmed higher diagnostic accuracy using the temporo-orbital WM reference. Pallidum [[18]F]PI-2620 showed significant associations with clinical disease severity exclusively when using the novel temporo-orbital WM reference.

CONCLUSIONS: A data-driven temporo-orbital WM reference optimizes [[18]F]PI-2620 PET assessment for PSP diagnosis, outperforming conventional cerebellar references used in tau-PET imaging.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00259-025-07396-8.},
}

@article {pmid41192695,
year = {2025},
author = {Kong, M and Xu, Z and Lu, H and Chen, Y and Zhang, Y and Jiang, X and Wang, P},
title = {ShengHui Decoction mitigates oxidative stress and neuroinflammation in AlCl3-induced AD zebrafish via activating Nrf2/HO-1 and inhibiting NF-κB signaling pathway.},
journal = {Journal of ethnopharmacology},
volume = {},
number = {},
pages = {120785},
doi = {10.1016/j.jep.2025.120785},
pmid = {41192695},
issn = {1872-7573},
abstract = {ShengHui decoction (SHD), a traditional Chinese herbal formula, has long been used clinically to mitigate Alzheimer's disease (AD), demonstrating significant efficacy in alleviating cognitive impairment. However, its molecular mechanisms remain insufficiently understood.

AIM OF THE STUDY: To clarify the effects of SHD on oxidative stress-related markers and inflammatory cytokines in an aluminum chloride (AlCl3)-induced zebrafish model of AD and as well as uncover its underlying mechanisms in alleviating oxidative stress and neuroinflammation..

MATERIALS AND METHODS: Ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was employed to identify the bioactive constituents of SHD. Behavioral tests and histopathological analyses were then conducted to evaluate the effects of SHD (0.74, 1.48, and 2.96 mg/mL) on apoptosis and amyloid-beta (Aβ) deposition in an AlCl3-induced AD zebrafish model. Biochemical assays and enzyme-linked immunosorbent assay were used to quantify superoxide dismutase (SOD), malondialdehyde (MDA), glutathione peroxidase (GSH-Px), tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), IL-1 beta (IL-1β), and IL-18.. Western blot analysis was performed to determine the protein expression of nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), NAD(P)H quinone dehydrogenase 1 (NQO1), nuclear factor-kappa B p65 (NF-κB p65), phosphorylated NF-κB p65 (p-NF-κB p65), and NOD-like receptor family pyrin domain containing 3 (NLRP3).

RESULTS: UPLC-MS/MS profiling identified phenolic acids, saponins, lignans/coumarins, flavonoids, and aliphatic alcohols as the main constituents of SHD. SHD significantly ameliorated cognitive deficits and histopathological abnormalities in AlCl3-induced zebrafish. Moreover, SHD attenuated oxidative stress by upregulating Nrf2, HO-1, and NQO1 expression, while downregulating AlCl3-induced levels of NF-κB p65, p-NF-κB p65, NLRP3 and pro-inflammatory factors.

CONCLUSIONS: SHD effectively improved cognitive performance and reduced AD-like pathological lesions in AlCl3-induced zebrafish. Importantly, SHD exhibits both antioxidant and anti-inflammatory activities by activating the Nrf2/HO-1 axis and inhibiting NF-κB signaling, thereby alleviating oxidative stress and neuroinflammatory responses in AD. These findings provide experimental evidence supporting SHD as a potential therapeutic agent for AD, and substantiate the traditional Chinese medicine principle of tonifying the kidney and replenishing essence in the treatment of AD.},
}

@article {pmid41192434,
year = {2025},
author = {Wagemann, O and Tesky, VA and Schall, A and Nübling, G and Wlasich, E and Hüer, T and Walendzik, A and Weitzel, M and Giebel, GD and Raszke, P and Wasem, J and Pantel, J and Levin, J},
title = {[A review and guideline for the adequate and interdisciplinary (socio-)medical care of people with Down syndrome and dementia development].},
journal = {Fortschritte der Neurologie-Psychiatrie},
volume = {},
number = {},
pages = {},
doi = {10.1055/a-2708-3648},
pmid = {41192434},
issn = {1439-3522},
support = {Projekt-Nr. 01VSF21030//Innovationsfonds des Gemeinsamen Bundesausschusses/ ; 022_EKEA.133//Else-Kröner-Fresenius-Stiftung/ ; },
abstract = {Alzheimer's disease (AD) is one of the most common neurodegenerative disorders in older age. Individuals with Down syndrome (DS) are at significantly increased risk due to trisomy 21 and the resulting overexpression of the amyloid precursor protein. Prevalence rates of AD-related dementia in DS (DSAD) reach up to 88% beyond the age of 65. Despite this, structured diagnostic and therapeutic guidelines for DSAD are lacking.A narrative review of current literature on etiology, diagnosis, treatment, and care pathways for DSAD was conducted. Currently employed dementia diagnostic standards were evaluated in regard to the specific needs of individuals with DS.Established diagnostic methods are applicable to individuals with DS but require adaptations regarding symptom recognition, test administration, and interpretation. Early awareness among caregivers and healthcare providers, as well as timely referral to specialized centers, is essential for accurate diagnosis and treatment planning.Improving care for individuals with DSAD requires close coordination between general healthcare services and specialized centers. This review highlights the medical, diagnostic, and structural challenges in suspected DSAD and provides practical recommendations for patient care. The proposed guideline aims to reduce uncertainties in clinical practice and support sustainable, needs-based care.},
}

@article {pmid41192010,
year = {2025},
author = {Yang, M and Wang, Z and Zhou, Q and Zhang, Q and Li, Y and Wang, Z},
title = {The adjunctive efficacy of repetitive transcranial magnetic stimulation with non-pharmacological interventions in cognitive disorders: A meta-analysis of randomized sham-controlled trials.},
journal = {Asian journal of psychiatry},
volume = {114},
number = {},
pages = {104758},
doi = {10.1016/j.ajp.2025.104758},
pmid = {41192010},
issn = {1876-2026},
abstract = {OBJECTIVE: This meta-analysis aimed to systematically evaluate the specific, adjunctive efficacy of repetitive transcranial magnetic stimulation (rTMS) when combined with non-pharmacological interventions-namely, transcranial direct current stimulation (tDCS), Tai Chi, or cognitive training (CT)-in patients with Alzheimer's disease (AD) or mild cognitive impairment (MCI). The goal is to isolate the net therapeutic contribution of rTMS beyond the effects of the base interventions alone.

METHODS: A comprehensive search of Chinese and English databases was conducted from their inception until April 26, 2025. Randomized controlled trials (RCTs) that compared "a non-pharmacological intervention plus active rTMS" versus "the same non-pharmacological intervention plus sham rTMS".This "add-on" study design was selected to precisely isolate the effect of rTMS. The risk of bias was assessed using the PEDro scale and Cochrane tools. Statistical analyses were performed using Review Manager 5.4 software.

RESULTS: 9 studies involving 391 participants were included. The pooled analysis revealed that the adjunctive use of rTMS was significantly superior to the sham control in improving global cognitive function at the immediate post-treatment assessment (SMD=0.38, 95 %CI[0.20,0.56], P < .001, n = 9). This benefit was consistent across the MMSE (SMD=0.38, n = 6), MoCA (SMD=0.37, n = 2), and ADAS-cog (SMD=0.39, n = 3) scores. Subgroup analysis suggested that the rTMS-tDCS combination might offer a short-term advantage in improving MMSE scores (MD=4.67, P = .008). Furthermore, the adjunctive effect of rTMS was sustained, as particularly evidenced by the ADAS-cog at follow-up (SMD=0.74, P = .02). The pooled analysis indicated that rTMS combined with non-pharmacological therapy demonstrated a short-term, sustained (4-8weeks) improvement in global cognitive function (SMD=0.34, 95 % CI[0.07, 0.60], P = .01). Subgroup analysis revealed that this sustained benefit reached statistical significance on the ADAS-cog scale (SMD = 0.41, 95 %CI[0.01, 0.81], P = .04) but showed a non-significant positive trend on the MMSE (SMD=0.26, 95 %CI[-0.19, 0.72], P = .26). However, a key limitation was that most studies did not systematically report outcomes related to activities of daily living or behavioral function.

CONCLUSION: The evidence indicates that rTMS as an adjunct to non-pharmacological interventions provides a significant specific effect on global cognitive function in patients with AD and MCI shortly after treatment, which may be sustained in the short-term. However, long-term follow-up data are extremely limited, and the effect on activities of daily living remains to be validated. The combination of rTMS and tDCS shows promise,but conclusions are constrained by the small number of studies,limited sample sizes,and heterogeneity in intervention protocols. Future large-scale studies incorporating long-term, standardized follow-up and assessments of daily living abilities are warranted to confirm the specific clinical value of rTMS as an augmentative therapy.},
}

@article {pmid41191186,
year = {2025},
author = {Zhang, Y and Liu, S and Xu, K and Shen, Y and Liu, Z and Wang, Y and Bai, Y and Wang, S},
title = {Repetitive transcranial magnetic stimulation for cognitive and emotional symptoms in neurodegenerative diseases: a systematic review and dose-response meta-analysis.},
journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology},
volume = {},
number = {},
pages = {},
pmid = {41191186},
issn = {1590-3478},
support = {2023ZX06C16//Heilongjiang Province Key Research and Development Project: Evidence-based Evaluation Study on the Interventions of Traditional Chinese Medicine at Key Stages of the Whole Cycle of Parkinson's Disease/ ; },
abstract = {OBJECTIVE: We summarized the existing clinical evidence of repetitive transcranial magnetic stimulation (rTMS) for cognitive and emotional symptoms in Parkinson's disease (PD) and alzheimer's disease (AD), and conducted a series of dose-response meta-analyses to determine the magnitude and curve relationship between pulse quantity changes and treatment effect sizes.

METHODS: We retrieved existing evidence from 5 databases and collected relevant results data on rTMS treatment for cognitive and emotional symptoms in PD and AD. We analyzed the data using R software to evaluate the effect size using MD or SMD and 95% confidence intervals (CI), used heterogeneity tests to evaluate the differences in efficacy among the evidence, and used restricted cubic splines (RCS) to fit the dose-response curve.

RESULTS: A total of 17 studies were included in this study. We found that the total pulse quantity showed a significant bell-shaped curve in MoCA (χ[2] = 6.82, df = 2, p = 0.03), HAMA (χ[2] = 9.16, df = 2, p = 0.01), and ADL (χ[2] = 8.22, df = 2, p = 0.01), with optimal effects achieved at 16153, 12138, and 17,237 pulses respectively-indicating that clinical application should control pulses within these ranges to avoid insufficient or excessive doses weakening efficacy. A significant upward curve was observed in MMSE (χ[2] = 12.94, df = 2, p = 0.001), meaning higher pulse counts (up to the 80,000-pulse upper limit in this study) may further improve basic cognitive function, providing a reference for dose adjustment in patients with cognitive impairment.

CONCLUSION: Our meta-analysis results show that rTMS exhibits significant efficacy in cognitive and emotional symptoms of PD and AD. The dose-response results show that the total pulse quantity in MoCA, HAMA, and ADL of PD and AD patients presents a typical bell-shaped curve, and a typical upward curve in MMSE. This indicates that there is a curve relationship between pulse stimulation quantity and efficacy, and the pulse stimulation quantity should be emphasized in the clinical application of rTMS.},
}

@article {pmid41191158,
year = {2025},
author = {Pal, B and Panda, S and Bashir, B and Vishwas, S and Chaitanya, M and Hussain, MS and Gupta, G and Kumbhar, P and Gupta, S and Singh, SK},
title = {Nanomedicine-enabled neuroprotection: therapeutic role of berberine in neurodegenerative diseases.},
journal = {Molecular biology reports},
volume = {53},
number = {1},
pages = {49},
pmid = {41191158},
issn = {1573-4978},
mesh = {Humans ; *Berberine/therapeutic use/pharmacology ; *Neurodegenerative Diseases/drug therapy/metabolism ; *Neuroprotective Agents/therapeutic use/pharmacology ; *Nanomedicine/methods ; Animals ; *Neuroprotection/drug effects ; Nanoparticles/chemistry ; Oxidative Stress/drug effects ; Blood-Brain Barrier/metabolism/drug effects ; },
abstract = {Neurodegenerative diseases (NDs), including Alzheimer's, Amyotrophic lateral sclerosis, Huntington's, and Parkinson's, present an increasingly widespread health burden globally with limited curative or treatment modalities, mostly having symptomatic attenuation. Berberine (BBR) is an isoquinoline alkaloid that occurs naturally and has been proposed as a potential neuroprotectant, since it has been found to exert multiple effects to modulate most of the pathological hallmarks of NDs, including neuroinflammation, oxidative stress, mitochondrial dysfunction, and protein aggregation. Although it shows promise, the practical utilization of BBR is marred by low oral bioavailability, high rate of oxidation, and low blood-brain barrier permeability. To combat these issues, recent developments in nanotechnology, especially in the use and creation of lipidic, inorganic, and polymeric nano-particles, have dramatically altered the pharmacokinetics and pharmacodynamics of BBR. This article summarizes recent advances in BBR-based nanoformulations and emphasizes the translational potential of BBR-based nanopreparations to improve treatment response in NDs. It also describes the molecular foundation of the neuroprotective effects of BBR and its possible place in clinical practice. Future nanocarrier development and investigation of BBR mechanisms will be essential to the development of the next generations of therapeutics in NDs.},
}

Humans
*Berberine/therapeutic use/pharmacology
*Neurodegenerative Diseases/drug therapy/metabolism
*Neuroprotective Agents/therapeutic use/pharmacology
*Nanomedicine/methods
Animals
*Neuroprotection/drug effects
Nanoparticles/chemistry
Oxidative Stress/drug effects
Blood-Brain Barrier/metabolism/drug effects

@article {pmid41189798,
year = {2025},
author = {Sudevan, ST and Oh, JM and Prabhakaran, P and Abdelgawad, MA and Ghoneim, MM and Al-Serwi, RH and Kim, H and Mathew, B},
title = {Inhibition of monoamine oxidase by fluorobenzyloxy chalcone derivatives.},
journal = {RSC advances},
volume = {15},
number = {50},
pages = {42376-42394},
pmid = {41189798},
issn = {2046-2069},
abstract = {Inhibition of monoamine oxidase-B (MAO-B) decelerates the breakdown of dopamine in the brain, consequently augmenting dopaminergic neurotransmission, which is a critical pathway for ameliorating motor symptomatology of Parkinson's disease (PD). Chalcones are widely recognized as the lead inhibitors of MAO-B and hold significant therapeutic value for PD. Inspired by safinamide's pharmacophoric features, the study focuses on designing, synthesizing, and evaluating a novel series of fluorinated benzyloxy chalcone derivatives as selective MAO-B inhibitors. Thirteen fluorobenzyloxy chalcone derivatives were synthesized and evaluated for their inhibition of monoamine oxidase (MAO). All compounds showed better inhibition of MAO-B than of MAO-A. Compound (E)1-(4-bromophenyl)-3-(2-((3-fluorobenzyl)oxy)phenyl)prop-2-en-1-one (FBZ13) most potently inhibited MAO-B with an IC50 value of 0.0053 μM, followed by (E)3-(2-((3-fluorobenzyl)oxy)phenyl)-1-(thiophen-2-yl)prop-2-en-1-one (FBZ6) (IC50 = 0.023 μM). The IC50 value of FBZ13 was 4.0 times lower than that of reference drug safinamide. All compounds showed weak MAO-A inhibition, FBZ13 and FBZ6 displayed exceptionally high selectivity for MAO-B. Kinetic studies confirmed that these two compounds function as competitive and reversible MAO-B inhibitors. Additionally, PAMPA results indicated excellent membrane permeability and CNS bioavailability for FBZ13 and FBZ6, highlighting their promise as central nervous system-active agents. In vitro antioxidant assays evaluated the activities of enzymes (SOD, CAT, GSH, and GPx) in human neuroblastoma cells exposed to lipopolysaccharide (LPS). Treatment with compounds FBZ6 and FBZ13 (10 μM each) significantly enhanced enzyme activities, mitigating LPS-induced oxidative stress. Lead compounds were stabilized in protein-ligand complexes by the π-π stacking, which enabled them to bind to the active site of hMAO-B effectively. These results suggest that FBZ6 and FBZ13 are potent reversible selective MAO-B inhibitors, and they can be used as potential agents for the treatment of neurological disorders such as Alzheimer's diseases and PD.},
}

@article {pmid41189652,
year = {2025},
author = {Guo, H and Yang, Z and Zhang, G and Lv, L and Zhao, X},
title = {Meta analysis of the diagnostic efficacy of transformer-based multimodal fusion deep learning models in early Alzheimer's disease.},
journal = {Frontiers in neurology},
volume = {16},
number = {},
pages = {1641548},
pmid = {41189652},
issn = {1664-2295},
abstract = {INTRODUCTION: This study aims to systematically evaluate the diagnostic efficacy of Transformer-based multimodal fusion deep learning models in early Alzheimer's disease (AD) through a Meta-analysis, providing a scientific basis for clinical applications.

METHODS: Following PRISMA guidelines, databases such as PubMed and Web of Science were searched, and 20 eligible clinical studies (2022-2025) involving 12,897 participants were included. Study quality was assessed using the modified QUADAS-2 tool, statistical analyses were performed with Stata 16.0, effect sizes were pooled via random-effects models, and subgroup analyses, sensitivity analyses, and publication bias tests were conducted.

RESULTS: Results showed that Transformer-based multimodal fusion models exhibited excellent overall diagnostic performance, with a pooled AUC of 0.924 (95% CI: 0.912-0.936), sensitivity of 0.887 (0.865-0.904), specificity of 0.892 (0.871-0.910), and accuracy of 0.879 (0.858-0.897), significantly outperforming traditional single-modality methods. Subgroup analyses revealed that: Three or more modalities achieved a higher AUC (0.935 vs. 0.908 for two modalities, p =0.012). Intermediate fusion strategies (feature-level, AUC=0.931) significantly outperformed early (0.905) and late (0.912) fusion (p <0.05 for both). Multicenter data improved AUC (0.930 vs. 0.918 for single-center, p =0.046), while sample size stratification (<200 vs. ≥200 cases) showed no significant difference (p =0.113). Hybrid Transformer models (Transformer +CNN) trended toward higher AUC (0.928 vs. pure Transformer 0.917, p =0.068) but did not reach statistical significance.

DISCUSSION: Notable studies included Khan et al.'s (2024) Dual-3DM[3]AD model (AUC=0.945 for AD vs. MCI) and Gao et al.'s (2023) generative network (AUC=0.912 under data loss), validating model robustness and feature complementarity. Sensitivity analysis confirmed stable results (AUC range: 0.920-0.928), and Egger's test (p =0.217) and funnel plot symmetry indicated no significant publication bias. Limitations included a high proportion of single-center data and insufficient model interpretability. Future research should focus on multicenter data integration, interpretable module development, and lightweight design to facilitate clinical translation. Transformer-based multimodal fusion models demonstrate exceptional efficacy in early AD diagnosis, with multimodal integration, feature-level fusion, and multicenter data application as key advantages. They hold promise as core tools for AD "early diagnosis and treatment" but require further optimization for cross-cohort generalization and clinical interpretability.},
}

@article {pmid41189641,
year = {2025},
author = {Nasrallah, IM and Polacek, C and Frech, FH and Tariot, PN and Vawter, J and Zabar, Y and Divers, C and Shang, WY and Geldmacher, DS and Towman, M and Reiter, H and Marshall, CD and Baldivieso, V and Jones, DR and Musiek, ES and Toyosaki, H and Tousi, B},
title = {Early Alzheimer's disease patient care pathway and health system readiness: A framework for integrated care.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {11},
number = {4},
pages = {e70162},
pmid = {41189641},
issn = {2352-8737},
abstract = {UNLABELLED: Alzheimer's disease (AD) is often underdiagnosed, especially at early stages when symptoms are mild, and patients may benefit from new and recently approved anti-amyloid therapies. An updated patient care pathway may facilitate timely diagnosis and intervention. We conducted a scan of published information and convened an expert panel of health care professionals to gain insights on early AD care pathways. We developed an Early AD Patient Care Pathway as an implementation guide that includes new diagnostic and treatment modalities and addresses needs and opportunities. The Early AD Patient Care Pathway focuses on patient identification, assessment, diagnosis, treatment, and management and monitoring. Operational readiness considerations aid pathway implementation and include evaluating and addressing gaps in program and business planning, technology, education and resources, access and reimbursement, and care coordination. The pathway is adaptable to health system needs and may be further tested and refined for sustainability.

HIGHLIGHTS: We analyzed published information and insights from subject matter experts on care pathways for early Alzheimer's disease.We identified opportunities to improve screening of at-risk patients, make appropriate specialist referrals, and ensure timely access and care coordination for diagnosis, treatment, and monitoring as a means of incorporating the latest diagnostics and therapy options.We developed a care pathway that promotes an integrated approach to patient care and is adaptable to various healthcare settings with input from subject matter experts.},
}

@article {pmid41189609,
year = {2025},
author = {Perneczky, R and Quevenco, FC and Hendrix, J and Epelbaum, S and Teunissen, C and van der Flier, WM and Suárez-Calvet, M and Shi, J and Mielke, MM and Iwatsubo, T and Palmqvist, S and Hansson, O},
title = {How can Alzheimer's disease blood-based biomarkers reach clinical practice?.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {17},
number = {4},
pages = {e70207},
pmid = {41189609},
issn = {2352-8729},
abstract = {INTRODUCTION: Alzheimer's disease (AD) diagnosis has been based largely on clinical symptoms, despite their limited sensitivity and specificity. Biomarker use was proposed to support a more accurate and timely diagnosis. However, neuroimaging or cerebrospinal fluid (CSF) is rarely used in primary care due to their perceived invasiveness, cost, and need for appropriate infrastructure. Blood-based biomarkers (BBMs) could represent an economical, minimally invasive alternative, but barriers exist to a seamless translation to the clinic.

METHODS: Ten international experienced AD clinicians and biomarker experts participated in a diagnostic roundtable to discuss the implementation of BBMs for diagnosing early symptomatic AD.

RESULTS: The participants proposed an optimal AD diagnostic pathway and highlighted three main gaps to implementing BBMs for early symptomatic AD diagnosis: limited real-world data, resource gaps, and system barriers.

DISCUSSION: Although BBMs could streamline the AD diagnostic pathway, further real-world evidence and collaboration among multiple stakeholders are needed.

HIGHLIGHTS: Early symptomatic Alzheimer's disease (AD) diagnosis improves treatment strategy and lowers costs.Currently available biomarkers are not widely used across all clinical settings.Blood-based biomarkers (BBMs) could be a cost-effective, minimally invasive alternative.BBMs could accelerate an accurate AD diagnosis.There are barriers to the inclusion of BBMs in clinical practice.},
}

@article {pmid41189255,
year = {2025},
author = {Sleiay, M and Almohammad, TY and Sleiay, B and Sadeq, D and Salibie, N and Alkarkoukly, M and Alsleba, AA and Albalkhi, S and Alchalabi, E and Kilooh, T and Alsmadi, N and Alobeid, A and Esber, H and Mousa, A and Hasan, Z and Alabdullah, Y and Tannous, E and Hamsho, RM and Abu Ras, N and Khanje, L and Khanje, K and Othman, AA},
title = {Assessing Alzheimer's disease knowledge in the Syrian population using the ADKS: A cross-sectional study.},
journal = {Medicine},
volume = {104},
number = {42},
pages = {e45045},
doi = {10.1097/MD.0000000000045045},
pmid = {41189255},
issn = {1536-5964},
mesh = {Humans ; Cross-Sectional Studies ; *Alzheimer Disease/psychology ; Female ; Syria ; *Health Knowledge, Attitudes, Practice ; Male ; Adult ; Surveys and Questionnaires ; Middle Aged ; Young Adult ; Adolescent ; },
abstract = {Alzheimer disease (AD), a leading neurodegenerative disorder, disproportionately affects women and presents increasing global socioeconomic challenges. Despite growing identification of modifiable risk factors, public knowledge about AD's causes and progression remains limited in many regions. This study assesses AD knowledge among Syrian adults using the Alzheimer Disease Knowledge Scale (ADKS) and examines demographic correlations. This study evaluates the level of AD knowledge in the Syrian population and identify demographic factors associated with knowledge levels. A cross-sectional study was conducted from June to August 2024 using the validated Arabic version of the ADKS. The questionnaire (30 true/false items across 7 domains) was distributed electronically to Syrian adults (≥18 years). Descriptive statistics, t tests, 1-way analysis of variance, Pearson correlation, and Welch t test were performed using Statistical Package for the Social Sciences version 27. Ethical approval was granted by Aleppo University (No. 2408), and informed consent was obtained. A total of 685 participants responded (69.5% aged 18-25; 72.3% university-educated). While knowledge was high in domains related to life impact and treatment, substantial gaps were observed in understanding preventive drugs (20.4% correct) and caregiving strategies (11.1%). Higher knowledge scores were significantly associated with higher education levels, accessing healthcare-related information, and having relatives with AD (P < .001). This first Syrian study utilizing the ADKS revealed moderate public knowledge of AD (mean score: 18.79/30). Key knowledge gaps in caregiving and treatment underscore the need for targeted educational campaigns. Outreach led by healthcare professionals is essential to enhance awareness, promote early diagnosis, and support caregivers of individuals with AD.},
}

Humans
Cross-Sectional Studies
*Alzheimer Disease/psychology
Female
Syria
*Health Knowledge, Attitudes, Practice
Male
Adult
Surveys and Questionnaires
Middle Aged
Young Adult
Adolescent

@article {pmid41188985,
year = {2025},
author = {Abouelmagd, ME and Almosilhy, NA and Makhlouf, HA and Hassan, AK and Osman, ASA and Hindawi, MD and Elshahat, A and Alnajjar, AZ and Mustafa, MMM and Abdelsalam, OK and Mady, A and Shaheen, A and Barrett, MJ and Negida, A},
title = {Comparative safety of cholinesterase inhibitors and memantine for dementia: a protocol for a network meta-analysis of randomized controlled trials.},
journal = {Systematic reviews},
volume = {14},
number = {1},
pages = {213},
pmid = {41188985},
issn = {2046-4053},
mesh = {Humans ; *Memantine/therapeutic use/adverse effects ; *Cholinesterase Inhibitors/adverse effects/therapeutic use ; Systematic Reviews as Topic ; Network Meta-Analysis as Topic ; Randomized Controlled Trials as Topic ; *Dementia/drug therapy ; Meta-Analysis as Topic ; Alzheimer Disease/drug therapy ; },
abstract = {BACKGROUND: Dementia is a growing public health concern, affecting over 55 million people worldwide, with Alzheimer's disease (AD) being the most prevalent cause. Cholinesterase inhibitors (ChEIs) and memantine remain the mainstay pharmacological treatment for AD and other dementias, despite their modest benefits and potential adverse effects. The safety profiles of these medications, particularly at different doses and formulations, remain inadequately explored, necessitating a comprehensive evaluation.

METHODS: This systematic review and network meta-analysis (NMA) will assess the safety of ChEIs (donepezil, galantamine, rivastigmine) and memantine in dementia treatment. We will include randomized controlled trials (RCTs) with ≥ 3 months of follow-up, evaluating adverse events (AEs), serious adverse events (SAEs), and treatment discontinuation rates. A comprehensive literature search will be conducted in PubMed, Scopus, Web of Science, and Cochrane Library, with additional searches in Google Scholar and reference lists of included studies. Data extraction will follow a standardized approach, and study quality will be assessed using the Cochrane risk-of-bias tool-2. A Frequentist or Bayesian NMA framework will be used to compare safety profiles, with heterogeneity assessed using the I[2] test.

DISCUSSION: By addressing gaps in prior NMAs, this study aims to provide an in-depth evaluation of safety outcomes associated with different ChEI and memantine doses and formulations across various dementia types. The findings will support clinicians in making informed treatment decisions and guide future research and policy development for dementia management.

PROSPERO (CRD42025642902).},
}

Humans
*Memantine/therapeutic use/adverse effects
*Cholinesterase Inhibitors/adverse effects/therapeutic use
Systematic Reviews as Topic
Network Meta-Analysis as Topic
Randomized Controlled Trials as Topic
*Dementia/drug therapy
Meta-Analysis as Topic
Alzheimer Disease/drug therapy

@article {pmid41186822,
year = {2025},
author = {Voronova, AD and Karsuntseva, EK and Shishkina, VS and Fursa, GA and Chadin, AV and Shport, SV and Stepanova, OV and Chekhonin, VP},
title = {Cell Therapy Is a New Treatment Option to Prevent Neurodegenerative Changes and Restore Cognitive Functions in Alzheimer's Disease (Review).},
journal = {Bulletin of experimental biology and medicine},
volume = {},
number = {},
pages = {},
pmid = {41186822},
issn = {1573-8221},
abstract = {This review considers cell therapy and possible mechanisms underlying beneficial effects of cells in prevention of neurodegenerative changes as a promising approach to the treatment of Alzheimer's disease. The results of using various types of cells in experimental models of Alzheimer's disease and their effect on the regeneration of the brain and recovery of cognitive functions are presented.},
}

@article {pmid41186808,
year = {2025},
author = {Jafni, S and Nagakanni, M and Indhirakumar, B and Rani, RKS and Preethi, S and Hemamalini, V and Vanathi, G and Saraswathy, SD and Devi, KP},
title = {Synergistic neuroprotective effects of Vitexin and Thymol against Okadaic acid-induced neurotoxicity: Computational and In vitro evaluation.},
journal = {Molecular biology reports},
volume = {53},
number = {1},
pages = {43},
pmid = {41186808},
issn = {1573-4978},
support = {CRG/2022/000847-G//Anusandhan National Research Foundation (ANRF)/ ; },
mesh = {*Neuroprotective Agents/pharmacology ; *Apigenin/pharmacology/metabolism ; *Thymol/pharmacology/metabolism ; Molecular Docking Simulation ; Drug Synergism ; Animals ; Mice ; Molecular Dynamics Simulation ; Neurons/drug effects/metabolism ; Blood-Brain Barrier/metabolism/drug effects ; Cell Survival/drug effects ; Alzheimer Disease/drug therapy/metabolism ; Cell Line, Tumor ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by dementia and inexorable loss of neurons. Despite extensive research, the currently approved drugs offer only limited efficacy which highlights the need for exploring novel synergistic natural compounds capable of mitigating multiple targets of AD.

METHODS AND RESULTS: This study evaluated the neuroprotective potential of the synergistic combination of Vitexin and Thymol using computational and in vitro model systems in N2a cells. Computational pharmacokinetic screening revealed the blood-brain barrier (BBB) permeability of thymol and 0.55 bioavailability score for Vitexin. Molecular docking studies showed higher binding affinity of Vitexin with JNK and Thymol with COX-1 and CAMK-II and 100 ns molecular dynamics simulation exhibited stable binding with sustained hydrogen bond and hydrophobic interactions. Based on the IC50 values [Vitexin (135.24 µg/ml, 312.9 µM) and Thymol (36.91 µg/ml, 245.7 µM)] and combination index (CI < 1) determined by the acetylcholinesterase (AChE) inhibition assay and checkerboard assay (performed with 15 different combinations) respectively, the effective combination (Vitexin 45.08 µg/ml; Thymol 7.382 µg/ml; CI = 0.53) was fixed for further studies. In okadaic acid (OA) induced neurotoxicity model, pre-treatment with the combination significantly increased the cell viability (88.36 ± 3.73%) (n = 3). Real-time PCR results revealed the upregulation of PP1 gene expression and modulation of MAPK family (MEK1/2, ERK1/2 and JNK), and other tau related kinases (GSK3β, CAMKII and P70 s6).

CONCLUSION: The above findings demonstrate that the combination of Vitexin and Thymol effectively protect the neuronal cells from OA induced cytotoxicity and modulate the hyperactivation of kinases, suggesting its potential in preventing tau hyperphosphorylation in AD conditions.},
}

*Neuroprotective Agents/pharmacology
*Apigenin/pharmacology/metabolism
*Thymol/pharmacology/metabolism
Molecular Docking Simulation
Drug Synergism
Animals
Mice
Molecular Dynamics Simulation
Neurons/drug effects/metabolism
Blood-Brain Barrier/metabolism/drug effects
Cell Survival/drug effects
Alzheimer Disease/drug therapy/metabolism
Cell Line, Tumor

@article {pmid41185525,
year = {2025},
author = {Liu, Q and Feng, E and Li, S and Zhu, Y and He, X and Xu, X and Zheng, T and Tian, Y},
title = {High-Efficient Raman Enhancement on Organic Semiconductor-Stabilized Perovskite Heterostructures for Guiding Early Theranostics of Alzheimer's Disease.},
journal = {Angewandte Chemie (International ed. in English)},
volume = {},
number = {},
pages = {e18319},
doi = {10.1002/anie.202518319},
pmid = {41185525},
issn = {1521-3773},
support = {2024YFC3406405//National Key Research and Development Program of China/ ; 22222405//National Natural Science Foundation of China/ ; 22393930//National Natural Science Foundation of China/ ; },
abstract = {Perovskites have recently emerged as attractive optoelectronic semiconductors due to tunable bandgap, large absorption coefficient, and long carrier lifetime, making it ideal as a kind of chemical-mechanism based surface-enhanced Raman scattering (SERS) substrates. However, perovskites generally demonstrate poor stability at ambient conditions, limiting their applications for SERS bioanalysis. Herein, we created a perovskite-based heterostructure through effectively passivating defects at the interface with hydrophobic organic semiconductors, which simultaneously enhanced the stability and efficiency of perovskite SERS substrate. The significant enhancement factor of 10[7] was mainly stemmed from the resonance Raman effect and the highly-efficient charge transfer process driven by a novel light-induced hot electron transfer mechanism in plasmon-free substrates previously never reported. This system was subsequently developed as an integrated theranostic SERS platform for miR-146a monitoring with a detection limit down to 0.2 fM, successfully guiding the early theranostics to enhance the therapeutic efficiency for Alzheimer's disease (AD). This work brings new light into the design of efficient and stable semiconductor SERS substrate and opens novel diagnosis and treatment options for AD.},
}

@article {pmid41185054,
year = {2025},
author = {Leung, LY and Tam, HL and Asiamah, N and Ho, JK},
title = {Effect of melatonin on cognitive function in adults with cognitive impairment: a multi-dimensional meta-analysis of randomized trials.},
journal = {Alzheimer's research & therapy},
volume = {17},
number = {1},
pages = {238},
pmid = {41185054},
issn = {1758-9193},
mesh = {Humans ; *Melatonin/therapeutic use/pharmacology ; *Cognitive Dysfunction/drug therapy/psychology ; Randomized Controlled Trials as Topic ; *Cognition/drug effects ; },
abstract = {BACKGROUND: Cognitive impairment leads to poor daily social and occupational functions and sleep disturbances. Approximately two-thirds of all individuals with mild cognitive impairment (MCI) experience sleep problems that further reduce cognitive function. Melatonin, a hormone secreted by the pineal gland, has proven effective in mitigating sleep problems and cognitive function in individuals with MCI. The current review investigated the efficacy of melatonin in improving cognitive function in adults with cognitive impairment.

METHODS: Seven databases were systematically searched for relevant randomized controlled trials published (in English or Chinese) until April 2025. Two reviewers independently selected studies, assessed quality (using the Physiotherapy Evidence Database scale), and extracted data.

RESULTS: In total, 394 potentially eligible articles were identified. Finally, 8 studies (518 participants) were included. Five, one, and two studies had good, excellent, and low quality, respectively. Pooled results indicated that melatonin significantly improved cognitive function in adults with cognitive impairment (mean difference [MD]: 1.08; p < 0.0001). Subgroup analyses by treatment duration, administration time, and cognitive impairment level revealed that the effects of melatonin were significant when it was administered for 13-24 weeks (MD: 2.04; p < 0.00001), between the times of 20:30 and 21:00 (MD: 2.2; p < 0.00001), and to individuals with MCI (MD: 2.63; p < 0.000001).

CONCLUSIONS: Our findings suggest that melatonin is relatively safe for individuals with cognitive impairment. Thus, we recommend it for adults with MCI. It should be administered between 20:30 and 21:00 for 13-24 weeks.},
}

Humans
*Melatonin/therapeutic use/pharmacology
*Cognitive Dysfunction/drug therapy/psychology
Randomized Controlled Trials as Topic
*Cognition/drug effects

@article {pmid41184619,
year = {2025},
author = {Choe, K and Ali, J and Park, HY and Jang, SH and Choi, EY and Kang, MH and Park, TJ and Kim, MO},
title = {The mGluR2/3 agonist xanthurenic acid improves memory, attention, and synaptic deficits by modulating glutamate release in Alzheimer's disease model.},
journal = {Acta pharmacologica Sinica},
volume = {},
number = {},
pages = {},
pmid = {41184619},
issn = {1745-7254},
abstract = {Amyloid-beta (Aβ) aggregation is the key component of neuritic plaques that drives Alzheimer's disease (AD) progression and cognitive decline. Although synaptic dysfunction strongly correlates with cognitive impairment, its underlying mechanisms remain unclear. Recently, the kynurenine pathway (KP) of tryptophan metabolism has emerged as a key contributor to AD pathology, and xanthurenic acid (XA), a naturally occurring end-product of the KP, has been implicated in neuroprotection. In this study, we investigated the neuroprotective effects of intranasally administered XA in an Aβ-induced AD mouse model. AD-like pathology was induced in mice by intracerebroventricular injection of Aβ1-42. The mice received daily intranasal instillation of XA (0.5 μg/5 μL per nostril) for 6 weeks. After XA treatment was completed, the cognitive performance was assessed in behavioral tests, then the mice were euthanized, and the brain were collected for molecular and biochemical analyses. We showed that XA treatment significantly improved the cognitive function of AD mice, and reduced AD-related pathological markers such as APP, Aβ and BACE-1 in the cortex, hippocampus and olfactory bulb. XA treatment also attenuated Aβ-induced oxidative stress through upregulation of the Nrf2/HO-1/SOD1 and key enzymatic antioxidants (GSH, GST, CAT, SOD), while concurrently reducing lipid peroxidation. Furthermore, XA treatment preserved synaptic integrity, evidenced by restoring both pre- and postsynaptic markers (SNAP-25, SYP, SNAP-23, PSD-95) and enhancing signaling via the cAMP-PKA-CREB pathway. Notably, XA differentially modulated metabotropic glutamate receptors, decreasing mGluR2 and increasing mGluR3 expression. In vitro experiments were conducted in APPswe/ind-transfected SH-SY5Y neuroblastoma cells. XA (3-100 µM) dose-dependently improved the cell viability while reducing cytotoxicity and apoptosis. Overall, these results demonstrate that XA confers multifaceted neuroprotection by modulating Aβ pathology, oxidative stress, synaptic function, and glutamatergic signaling, suggesting its potential as a novel therapeutic strategy to mitigate cognitive decline and pathological progression in AD.},
}

@article {pmid41184442,
year = {2025},
author = {Garnier-Crussard, A and Landeau, B and Mezenge, F and Gonneaud, J and Roquet, D and Cotton, F and Chetelat, G},
title = {Heterogeneity of white matter hyperintensities in Alzheimer's disease captured by multimodal neuroimaging.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {38433},
pmid = {41184442},
issn = {2045-2322},
support = {667696//European Union's Horizon 2020 Research and Innovation Program/ ; 667696//European Union's Horizon 2020 Research and Innovation Program/ ; },
mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/pathology/metabolism ; *White Matter/diagnostic imaging/pathology/metabolism ; Aged ; Male ; Female ; *Neuroimaging/methods ; *Multimodal Imaging/methods ; Positron-Emission Tomography ; Aged, 80 and over ; Magnetic Resonance Imaging ; Fluorodeoxyglucose F18 ; },
abstract = {White matter hyperintensities (WMH) are common in older adults and are associated with cognitive disorders. They typically arise from small vessel disease, leading to demyelination and axonal loss. WMH are thus considered markers of cerebrovascular changes. However, other pathophysiological processes can lead to WMH, particularly in Alzheimer's disease (AD). Understanding the diverse origins of WMH could enhance the diagnosis and treatment of AD patients. We hypothesize that multimodal neuroimaging could help understand the heterogeneity of WMH and pinpoint their specific origin. We included 142 older adults from the community and memory clinic (with an emphasis on patients within the Alzheimer's continuum), and tested if multimodal neuroimaging signal within regional WMH (including T1w, T2w, [18]F-florbetapir [AV45] and [18]F-fluorodeoxyglucose [FDG] PET), is associated with amyloid load and cognition. We showed that intra-WMH T1w and T2w signal in the parietal and frontal lobes were linked to amyloid status; intra-WMH T2w signal in all regions negatively correlated with amyloid load, while intra-WMH T1w signals in the parietal lobe positively correlated with amyloid load; finally, intra-WMH T1w signal negatively correlated with cognition while T2w and marginally AV45 signals positively correlated with cognition. This study demonstrates the potential of multimodal neuroimaging to unravel the heterogeneity of WMH, which could enhance their interpretation and improve clinical decision-making.},
}

Humans
*Alzheimer Disease/diagnostic imaging/pathology/metabolism
*White Matter/diagnostic imaging/pathology/metabolism
Aged
Male
Female
*Neuroimaging/methods
*Multimodal Imaging/methods
Positron-Emission Tomography
Aged, 80 and over
Magnetic Resonance Imaging
Fluorodeoxyglucose F18

@article {pmid41183995,
year = {2025},
author = {Okamura, N and Nakayama-Naono, R and Harada, R},
title = {[In vivo imaging of Alzheimer's disease lesion].},
journal = {Nihon yakurigaku zasshi. Folia pharmacologica Japonica},
volume = {160},
number = {6},
pages = {398-403},
doi = {10.1254/fpj.25055},
pmid = {41183995},
issn = {0015-5691},
mesh = {*Alzheimer Disease/diagnostic imaging ; Humans ; Animals ; Positron-Emission Tomography ; Amyloid beta-Peptides/metabolism ; },
abstract = {In the development of Alzheimer's disease (AD) therapeutics, positron emission tomography (PET) imaging techniques play an important role in the selection of patients for administration and objective evaluation of treatment effects. The clinical implementation of amyloid-β (Aβ) and tau PET agents is progressing, with the aim of noninvasively visualizing brain lesions in AD. Furthermore, the development of PET agents for imaging neuroinflammation is advancing. Near-infrared fluorescence (NIRF) imaging has attracted attention as an alternative technology to nuclear imaging. Near-infrared light in the wavelength range of 650-900 nm, known as the optical window, is absorbed less by living tissue compared to visible light. Therefore, by using probes that emit NIRF, it is possible to noninvasively measure the distribution of probes within the body. Indocyanine green (ICG), a non-specific NIRF probe, is already being used in surgical procedures, but NIRF probes specifically for AD lesions are still in the developmental stage. The characteristics required for NIRF Aβ probe include high binding affinity and selectivity for Aβ, excitation and fluorescence wavelengths in the optical window, and blood-brain barrier permeability. Numerous NIRF probes for Aβ have been developed, reaching levels suitable for use in animal experiments. In recent years, research has also progressed on the development of multi-target fluorescence imaging probes that can identify multiple targets with a single probe by utilizing differences in fluorescence wavelengths according to the binding targets.},
}

*Alzheimer Disease/diagnostic imaging
Humans
Animals
Positron-Emission Tomography
Amyloid beta-Peptides/metabolism

@article {pmid41183202,
year = {2025},
author = {Yang, X and Lee, JY and Moghadam, F and Steiner, J and Kim, SK and Ganjur, N and de Almenara, AJ and Stoltz, BM and Loh, YP and Goddard, WA},
title = {Predicted molecules followed by experimental validation for protecting human neurons from oxidative stress-induced cytotoxicity.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {122},
number = {45},
pages = {e2505359122},
doi = {10.1073/pnas.2505359122},
pmid = {41183202},
issn = {1091-6490},
support = {no numbef//HHS | NIH | Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)/ ; R01HL155532 R35HL150807 and R35GM145239//HHS | NIH (NIH)/ ; CAP23011-200//National Research Council of Science and Technology (NST)/ ; },
mesh = {Humans ; *Oxidative Stress/drug effects ; *Neurons/drug effects/metabolism/pathology ; *Neuroprotective Agents/pharmacology/chemistry ; Animals ; },
abstract = {Alzheimer neurodegenerative disease (AD) has had a major impact worldwide, with no effective drugs for treatment. We discovered and reported earlier that neurotrophic factor-α1 (NF-α1)/carboxypeptidase E (CPE) reversed neurodegeneration and cognitive dysfunction in AD mouse models. We then predicted computationally and validated experimentally that CPE interacts with a pharmacophore of six residues on the 5-HT1E receptor (HTR1E) to activate the ERK-BCL2 signaling pathway leading to protection of human neurons against oxidative stress-induced cell death. We now report using this pharmacophore for in silico virtual screening of ~6 million small molecules to discover candidates with similar binding and neuroprotective properties as CPE. This in silico search identified a molecule (Z124) that was verified experimentally to bind to HTR1E with protective efficacy comparable to NF-α1/CPE but requiring a higher concentration. Next, we carried out R-group design optimization based on Z124 to identify 4 compounds predicted to have much better efficacy than Z124. These compounds were synthesized and tested for neuroprotective activity. All four compounds showed binding to HTLA-HTR1E cells comparable to CPE. We determined the Kd for two of these compounds: R9, 1.38 ± 0.2 nM, and R10, 2.1 ± 0.2 nM, to be over 15 times better than CPE. Furthermore, all four new compounds showed protective activity against oxidative stress-induced cytotoxicity in human HEK293 cells stably transfected with HTR1E, as well as human primary neurons. Mechanistically, R9 and R10 activated ERK phosphorylation and increased the mitochondria prosurvival protein, BCL2, making them excellent candidates for further development as a drug to treat neurodegenerative diseases.},
}

Humans
*Oxidative Stress/drug effects
*Neurons/drug effects/metabolism/pathology
*Neuroprotective Agents/pharmacology/chemistry
Animals

@article {pmid41183099,
year = {2025},
author = {Liu, J and Zhang, ZZ and Yu, GR and Han, X},
title = {Quercetin Targets HSP90α and Regulates Keap1/Nrf2 Pathway to Inhibit Crosstalk between Apoptosis and Ferroptosis in Oxidatively Stressed Neurons.},
journal = {Journal of biochemical and molecular toxicology},
volume = {39},
number = {11},
pages = {e70583},
doi = {10.1002/jbt.70583},
pmid = {41183099},
issn = {1099-0461},
support = {//This study was supported by the National Key Research and Development Program of China (2022YFC3501400) and Jiangsu Province Graduate Practice and Innovation Program (SJCX25_0998)./ ; },
mesh = {*Quercetin/pharmacology ; *HSP90 Heat-Shock Proteins/metabolism ; *NF-E2-Related Factor 2/metabolism ; *Kelch-Like ECH-Associated Protein 1/metabolism ; *Ferroptosis/drug effects ; *Oxidative Stress/drug effects ; *Neurons/metabolism/pathology/drug effects ; *Apoptosis/drug effects ; *Signal Transduction/drug effects ; Humans ; Animals ; },
abstract = {The rising incidence and mortality rates associated with Alzheimer's disease (AD) have garnered significant attention. The interplay between ferroptosis and apoptosis, both of which are driven by oxidative stress, contributes to neuronal death and accelerates the progression of AD. In this study, we observed that neuronal cells exhibited characteristics of both ferroptosis and apoptosis following exposure to a specific concentration of hydrogen peroxide; both processes could be effectively inhibited by quercetin. To further investigate the precise mechanisms, we conducted target enrichment analysis utilizing databases pertinent to quercetin, AD, oxidative stress, ferroptosis, and apoptosis. Our findings identified HSP90AA1 as a potential key target through which quercetin disrupts the interplay between ferroptosis and apoptosis. We subsequently focused on HSP90α, encoded by HSP90AA1, and validated its role in ferroptosis and apoptosis using HSP90α and Nrf2 inhibitors. Our results demonstrate that under oxidative stress conditions, quercetin induces the activation of HSP90α. This activated chaperone binds to kelch-like ECH-associated protein 1 (Keap1), which disrupts the Keap1-Nrf2 complex and facilitates the release of nuclear factor erythroid 2-related factor 2 (Nrf2). The liberated Nrf2 translocates to the nucleus, initiating the expression of cytoprotective genes. Once in the nucleus, Nrf2 activates the Glutathione peroxidase 4 (GPX4) pathway and the expression of B-cell lymphoma-2 (Bcl-2) family proteins to inhibit ferroptosis and apoptosis. This study elucidates the crosstalk mechanism by which quercetin modulates neuronal ferroptosis and apoptosis under oxidative stress, providing new insights and potential therapeutic targets for the prevention and treatment of AD.},
}

*Quercetin/pharmacology
*HSP90 Heat-Shock Proteins/metabolism
*NF-E2-Related Factor 2/metabolism
*Kelch-Like ECH-Associated Protein 1/metabolism
*Ferroptosis/drug effects
*Oxidative Stress/drug effects
*Neurons/metabolism/pathology/drug effects
*Apoptosis/drug effects
*Signal Transduction/drug effects
Humans
Animals

@article {pmid41182777,
year = {2025},
author = {Thomas, ML and Edland, SD and Duehring, J},
title = {The MMSE can yield biased and imprecise estimates of change: A novel IRT analysis of latent change scores from the A4 clinical trial.},
journal = {Psychological assessment},
volume = {},
number = {},
pages = {},
doi = {10.1037/pas0001426},
pmid = {41182777},
issn = {1939-134X},
support = {//National Institutes of Health; National Institute of Mental Health/ ; },
abstract = {The measurement precision of change scores has previously been investigated from the perspective of classical test theory. However, the measurement precision of change scores has not been thoroughly explored from an item response theory (IRT) perspective. In this study, we provide, to our knowledge, one of the first direct investigations of change score precision within an IRT framework. Specifically, using archival data from the antiamyloid treatment in asymptomatic Alzheimer's trial, we examined standard error of estimate for change scores on the mini-mental state examination, one component of the preclinical Alzheimer cognitive composite used to measure change between intervention arms. Multidimensional two-parameter IRT models were fitted to the mini-mental state examination item data with one latent dimension reflecting baseline ability and a second reflecting change in ability over time (i.e., latent change scores). Results showed that standard error depended on change magnitude and that change scores were expected to be biased toward zero when baseline performance scores were near ceiling. The results demonstrate why measures with pronounced ceiling effects should not be used to assess change in clinical trials or other longitudinal studies, and should be used cautiously in clinical settings. This study also demonstrates how IRT can be used to evaluate change score precision. (PsycInfo Database Record (c) 2025 APA, all rights reserved).},
}

@article {pmid41182353,
year = {2025},
author = {Cai, Y and Huang, S and Dong, Y and Li, S and Jin, X},
title = {PIWI-Interacting RNAs in brain health and disease: biogenesis, mechanisms, and therapeutic horizons.},
journal = {Psychopharmacology},
volume = {},
number = {},
pages = {},
pmid = {41182353},
issn = {1432-2072},
support = {81971083//National Natural Science Foundation of China/ ; 25JCLZJC00190//Tianjin Natural Science Foundation Project/ ; },
abstract = {PIWI-interacting RNAs (piRNAs), a class of small non-coding RNAs originally identified for their role in transposon silencing in germ cells, have recently been recognized as pivotal regulators of gene expression in the central nervous system. Beyond their canonical functions in genome defense, emerging evidence highlights piRNAs as key modulators of neuronal development, synaptic plasticity, axonal regeneration, and neuroimmune interactions-processes central to brain function and dysfunction. This review provides a comprehensive overview of piRNA biogenesis, molecular mechanisms, and regulatory pathways relevant to neurobiology. We focus on the growing body of evidence implicating piRNA dysregulation in major neurological and neuropsychiatric disorders, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, stroke, glioma, autism spectrum disorder, and schizophrenia. Importantly, we discuss the neuropharmacological implications of piRNA pathways as novel targets for therapeutic intervention and their potential utility as biomarkers for early diagnosis and treatment stratification. By integrating mechanistic insights with emerging translational evidence, this review highlights piRNAs as promising molecular targets in the development of next-generation neurotherapeutics aimed at modifying disease progression and improving brain health.},
}

@article {pmid41181807,
year = {2025},
author = {Richardson, DL and Whitney, E},
title = {Deep Brain Stimulation: Overview and Applications in the Context of Neuropsychiatric Conditions.},
journal = {Cureus},
volume = {17},
number = {10},
pages = {e93661},
pmid = {41181807},
issn = {2168-8184},
abstract = {Deep brain stimulation (DBS) is a neuromodulatory therapy involving the implantation of electrodes into brain structures in order to help normalize brain activity in a variety of neurological disorders. The mechanisms of DBS operate at micro-, meso-, and macroscale levels to influence neuronal signaling, synaptic reorganization, and network-wide connectivity between brain regions. Recent advances in connectomics and sensing technologies have allowed for more precise and adaptive stimulation strategies, increasing the potential to target complex, heterogeneous neuropsychiatric conditions. DBS has already been well-explored as a treatment for obsessive-compulsive disorder. Emerging research has explored the use of DBS for other neuropsychiatric conditions as well, including autism spectrum disorder (ASD), treatment-refractory depression (TRD), and dementia associated with Alzheimer's disease (AD). DBS for ASD shows promise in reducing self-injurious behaviors and aggression by targeting the nucleus accumbens (NAc), amygdala, and posteromedial hypothalamus. In TRD, DBS to the subcallosal cingulate gyrus (SCG), medial forebrain bundle (MFB), and ventral capsule/ventral striatum (VC/VS) has demonstrated significant antidepressant effects. For dementia and AD, DBS targeting the fornix and nucleus basalis of Meynert (NBM) has shown promise in slowing cognitive decline. Despite the variety of targets, connectomic analyses reveal overlapping cortical-subcortical network dysfunctions across these disorders. These findings offer insight into shared neurobiological mechanisms of these disorders, as well as guide refinement of therapeutic targets for future study. Overall, DBS for neuropsychiatric conditions remains in its early stages, hindered by disorder heterogeneity and challenges in identifying optimal brain targets. Advances in functional neuroimaging, closed-loop stimulation, and machine learning-driven connectomic approaches can aid in target selection as well as better understanding the neuroanatomy and physiology underlying these complex conditions, which, in turn, lead to improved patient outcomes. Further research is necessary to establish standardized protocols and expand the therapeutic applications of DBS in neuropsychiatry.},
}

@article {pmid41180952,
year = {2025},
author = {Zammit, M and Price, J and Christian, B and Rafii, M and , },
title = {A comparison of multiple amyloid PET radiotracers for Down syndrome clinical trials.},
journal = {Brain communications},
volume = {7},
number = {6},
pages = {fcaf406},
pmid = {41180952},
issn = {2632-1297},
abstract = {Adults with Down syndrome carry high risk of developing Alzheimer's disease and efforts to include this population in clinical trials remain limited. A barrier to recruitment for anti-amyloid trials includes the availability of the same amyloid PET radiotracer to multiple treatment centres. The objective of the study is to compare longitudinal rates of change between different amyloid PET radiotracers, particularly Pittsburgh compound B and florbetapir, in Down syndrome and to compare the estimated age at amyloid-positivity derived from these radiotracers. Two hundred thirty-seven adults with Down syndrome from the Trial Ready Cohort-Down syndrome and Alzheimer's Biomarker Consortium-Down syndrome studies were imaged using T1-weighted MRI and using PET images of Pittsburgh compound B, florbetapir, NAV4694 or flutemetamol to screen for amyloid plaque burden. Currently, Pittsburgh compound B and florbetapir have longitudinal data from these cohorts, while NAV4694 has one individual with longitudinal scans and flutemetamol has no available longitudinal data. Pittsburgh compound B displayed a greater effect size to measure amyloid change compared to florbetapir. NAV4694 and Pittsburgh compound B, which are structurally similar compounds, displayed similar sensitivity to measure longitudinal amyloid increase. The estimated age at amyloid onset showed no significant difference between Pittsburgh compound B, florbetapir, NAV4694 or flutemetamol. The findings suggest that different amyloid PET radiotracers provide consistent estimates of amyloid onset age for adults with Down syndrome. Multicentre studies of Alzheimer's disease therapeutics can utilize multiple amyloid PET radiotracers to facilitate recruitment; however, these radiotracers have different sensitivity to detect longitudinal change.},
}

@article {pmid41180843,
year = {2025},
author = {Ceccarelli, MC and Lai, L and Carmignani, A and Battaglini, M and Ciofani, G},
title = {Polydopamine nanoparticles as immunomodulators: inhibition of M1 microglial polarization.},
journal = {Frontiers in bioengineering and biotechnology},
volume = {13},
number = {},
pages = {1672520},
pmid = {41180843},
issn = {2296-4185},
abstract = {Neuroinflammation is a central feature of numerous neurodegenerative diseases, including Alzheimer's and Parkinson's disease, where excessive activation of microglia can contribute to neuronal damage. The pro-inflammatory M1 phenotype of microglia is characterized by increased production of reactive oxygen species (ROS), overexpression of surface markers such as CD40 and CD86, and secretion of cytokines like IL-6, IL-8, and TNF-α, all of which exacerbate oxidative stress and neurodegeneration. The development of strategies to control and tune microglial pro-inflammatory activation is therefore critical for reducing the progression of these conditions. In this study, the potential of polydopamine nanoparticles (PDNPs) as novel immunomodulatory agents for attenuating M1 microglial polarization was investigated. PDNPs were synthesized via a simple and reproducible protocol and thoroughly characterized in terms of size, morphology, hydrodynamic diameter, and surface charge, confirming their uniformity and stability. Biocompatibility assays showed that PDNPs are well tolerated by human microglial clone 3 (HMC3) cells, with minimal cytotoxicity even at relatively high concentrations. Confocal microscopy and flow cytometry analyses demonstrated efficient internalization of PDNPs by microglia, with preferential accumulation in lysosomal compartments and negligible mitochondrial localization. To mimic neuroinflammatory conditions, HMC3 cells were stimulated with interferon-gamma (IFN-γ), which significantly increased intracellular ROS levels, surface expression of CD40 and CD86, and secretion of pro-inflammatory cytokines. The co-treatment with PDNPs effectively mitigated these effects by reducing oxidative stress, suppressing the upregulation of M1 markers, and decreasing cytokine release, thereby preventing the shift toward a pro-inflammatory state. The results of this work demonstrate that PDNPs not only exhibit excellent biocompatibility and cellular uptake but also provide a robust means of counteracting IFN-induced microglial activation. These results establish PDNPs as promising nanoplatforms for modulating neuroinflammation and microglial activation. This study highlights the potential of PDNPs for future applications in the treatment of neurodegenerative diseases.},
}

@article {pmid41179212,
year = {2025},
author = {Yuan, C and Lv, S and Han, Y and Li, Y and Xian, Z and Liu, G and Xiao, S},
title = {Quercetagitrin Ameliorates Alzheimer-Like Pathologies Associated with TNFα/NFκB Pathway in APP/PS1 Mice.},
journal = {ACS omega},
volume = {10},
number = {42},
pages = {49816-49827},
pmid = {41179212},
issn = {2470-1343},
abstract = {Background: Alzheimer's disease (AD) is a neurodegenerative disease with two pathological features in the brain: amyloid β (Aβ) plaques and tau tangles. Neuroinflammation plays an important role in the development of AD, closely related to both Aβ and tau pathologies. Tumor necrosis factor α (TNFα) and nuclear factor-κB (NFκB) behave as key regulators of neuroinflammation in AD. It is pressing to develop effective AD drugs. Objective: This study aimed to explore the effects and mechanisms of quercetagitrin in AD using a combination of network pharmacology analyses and in vivo experiments. Methods: The potential target of quercetagitrin in AD was predicted by network pharmacology. The interaction between the compound and the target protein was measured by molecular docking. The in vivo effects were performed in APP/PS1 mice via mouse behavior tests, Western blotting, ThS staining, immunohistochemical staining, and immunofluorescence staining. Results: First, network pharmacology analyses were conducted to predict the primary target of the compound, which is TNFα. Then, molecular docking showed that quercetagitrin interacts with TNFα with a high affinity. Finally, the level of TNFα was reduced, and the activation of NFκB signaling was inhibited by quercetagitrin in APP/PS1 mice. Meanwhile, quercetagitrin treatment ameliorated Aβ pathology, cognitive impairments, and neuroinflammation in the AD mice. Conclusions: These findings demonstrate quercetagitrin as a potential therapeutic drug for AD.},
}

@article {pmid41179172,
year = {2025},
author = {da Silva, LRG and de Sá, CB and do Amaral, BS and Romeiro, NC and Cass, QB and Valverde, AL},
title = {Affinity Selection-Mass Spectrometry for the Identification of Ligands of Acetylcholinesterase from Topsentia ophiraphidites and Docking Studies for the Dereplicated Ligands.},
journal = {ACS omega},
volume = {10},
number = {42},
pages = {50275-50284},
pmid = {41179172},
issn = {2470-1343},
abstract = {Acetylcholinesterase (AChE) inhibition has been successful for the treatment of Alzheimer's disease and still stands as an important target in the search for novel ligands. In this context, affinity selection-mass spectrometry (AS-MS) has been acknowledged as a high-throughput screening (HTS) technique for large molecular libraries in drug discovery programs and natural product investigations. In this work, an AS-MS assay with AChE immobilized onto magnetic beads (AChE-MB) has been used to search for ligands in samples of the sponge Topsentia ophiraphidites collected in the archipelago of Fernando de Noronha, Brazil. Ligand dereplication disclosed 6-desmethyl-6-ethyl-9,10-dihydrospongosoritin A, 3,5-dibromo-O-methyltyrosine, 3-bromo-5-iodo-O-methyltyrosine, and 3,5-di-iodo-O-methyltyrosine as AChE ligands, which showed affinity ratios of 1.84, 1.34, 1.26, and 1.20, respectively, in the AS-MS assay. As a complementary approach, molecular docking analysis with human AChE has been carried out for the disclosed dereplicated ligands, in which the (R, R) stereoisomer of 6-desmethyl-6-ethyl-9,10-dihydrospongosoritin A stood out, performing important intermolecular interactions with the active sites of AChE, especially with the peripheral anionic site, at the entrance of the gorge. The results stimulate further investigations of these ligands in other pharmacological assays in order to better understand their mechanisms of action.},
}

@article {pmid41178976,
year = {2025},
author = {Bae, HJ and Kim, SI and Kim, SY and Cho, YE and Sung, S and Lim, S and Cho, K and Park, SJ and Lim, S},
title = {Lacticaseibacillus rhamnosus CBT LR5 with skim milk alleviates scopolamine-induced cognitive impairment in mice.},
journal = {Frontiers in microbiology},
volume = {16},
number = {},
pages = {1672153},
pmid = {41178976},
issn = {1664-302X},
abstract = {INTRODUCTION: Emerging evidence highlights the gut-brain axis as a pivotal pathway linking gastrointestinal health with cognitive function, particularly in neurodegenerative conditions such as Alzheimer's disease (AD).

METHODS: This study investigated the cognitive-enhancing effects of the probiotic strain Lacticaseibacillus rhamnosus CBT LR5 (LR5), alone or in combination with skim milk, in a mouse model of scopolamine-induced cognitive impairment. The cognitive functions were evaluated using the novel object recognition test (NOR) and the passive avoidance test (PAT).

RESULTS: The results demonstrated that the oral administration of LR5, especially when combined with skim milk, significantly ameliorated scopolamine-induced cognitive deficits. Mechanistically, treatment with LR5 combined with skim milk restored the diversity and composition of the gut microbiota increased the abundance of beneficial genera, such as Muribaculaceae and enhanced intestinal barrier integrity by increasing the expression of tight junction proteins, including claudin-1, occludin, and zonula occludens-1. Additionally, this combination reduced systemic inflammation by lowering serum TNF-α and PGE2 levels and promoted increased expression of BDNF by activating the CREB-BDNF-TrkB signaling pathway in hippocampal and cortical tissues. Furthermore, correlation analyses revealed significant associations between specific gut bacterial genera, such as Lacticaseibacillus, Turicibacter, Cryptobacteroides, Ruminococcus, and Muribaculaceae, and cognitive or inflammatory biomarkers.

DISCUSSION: Collectively, these findings suggest that the synergistic effects of L. rhamnosus CBT LR5 combined with skim milk may represent an effective dietary intervention for cognitive enhancement, potentially through gut microbiota modulation, improved barrier integrity, reduced inflammation, and enhanced neurotrophic signaling.},
}

@article {pmid41178777,
year = {2025},
author = {Yigitturk, G and Cavusoglu, T},
title = {A Review of The Place of Adipose-Derived Stem Cells among Stem Cell Applications in Neurodegenerative Diseases.},
journal = {Current topics in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115680266363649250620113954},
pmid = {41178777},
issn = {1873-4294},
abstract = {Treatment of neurodegenerative diseases aims to slow disease progression, alleviate symptoms, and improve life quality. Adipose-Derived Stem Cells (ADSCs) have emerged as a promising treatment for neurodegenerative diseases that can be easily obtained from adipose tissues. Their abundance, accessibility, and potential for multilinear differentiation make them an attractive candidate for regenerative medicine. ADSCs can release neurotrophic factors, modulate neuroinflammation, and potentially differentiate into neurons, giving hope for neuronal repair and replacement. Preclinical studies have shown the efficacy of several neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, and spinal cord injuries. ADSC has demonstrated the potential to improve functional results, promote neurogenesis, induce tissue integrity, and reduce neuron loss. Clinical trials are still underway, but evidence of the effectiveness of ADSC in neurodegeneration is still being developed. The first clinical studies focused on safety and feasibility and achieved promising results. Optimizing cell transmission, controlling tumor growth, standardizing treatment protocols and such challenges remain. Current research is aimed at addressing these obstacles and transforming ADSC therapy into a widespread clinical practice. This review focuses on the characteristics, problems, and future approaches of ADSC in the context of neurodegenerative diseases and therapeutic processes.},
}

@article {pmid41178581,
year = {2025},
author = {Şen, İ and Yeşildal, TK and Abdulqadir, AH and Yaman, İ and Tosun, SN and Zengin, G and Cakmak, YS},
title = {Comprehensive evaluation of Onosma rostellatum: antioxidant, enzyme inhibitory and anticancer properties of root and leaf extracts.},
journal = {Journal of the science of food and agriculture},
volume = {},
number = {},
pages = {},
doi = {10.1002/jsfa.70284},
pmid = {41178581},
issn = {1097-0010},
support = {//Türkiye Bilimsel ve Teknolojik Araştırma Kurumu/ ; },
abstract = {BACKGROUND: The incidence and mortality of diseases such as cancer, Alzheimer's, and diabetes have increased in recent years. Along with limited treatment success, severe side effects of synthetic drugs are a major concern. Therefore, natural bioactive compounds are gaining attention as alternative therapeutic agents due to their efficacy and lower toxicity. This study investigated the protective and therapeutic potential of extracts of different parts of Onosma rostellatum, a plant used in traditional medicine, in terms of their antioxidant, enzyme inhibitory and anticancer activities.

RESULTS: Antioxidant, enzyme inhibition, anticancer activities and phenolic composition of the extracts were evaluated. Methanol leaf extract showed the strongest activity in antioxidant assays, with the highest 2,2-diphenyl-1-picrylhydrazyl (46.59 ± 0.03 g Trolox equivalents (TE) kg[-1]) and ferric reducing antioxidant power (90.74 ± 0.59 g TE kg[-1]) activities, while the root methanol extract exhibited the strongest 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid radical scavenging activity (453.86 ± 2.20 g TE kg[-1]) and the highest cupric reducing antioxidant capacity value (243.64 ± 0.49 g TE kg[-1]). The aqueous leaf extract demonstrated superior metal-chelating ability (32.59 ± 0.13 g ethylenediaminetetraacetic acid kg[-1]). Leaf extracts displayed the highest copper ion reducing capacity (94.64 ± 0.23 g TE kg[-1]). Ethyl acetate leaf extracts showed the most significant inhibition against α-amylase and α-glucosidase. High-performance liquid chromatographic analysis revealed rosmarinic acid and quercetin as major phenolic constituents. In cell culture experiments, the ethyl acetate leaf extract demonstrated the most potent anticancer effect, with an IC50 value of 167.2 ± 0.32 μg mL[-1] after 72 h.

CONCLUSION: Onosma rostellatum extracts possess strong antioxidant, enzyme inhibitory and anticancer activities, largely associated with their phenolic components. These findings highlight the potential of this plant as a natural source of therapeutic agents. © 2025 Society of Chemical Industry.},
}

@article {pmid41178110,
year = {2025},
author = {Polk, S and Rassaeikashuk, M and Thilagavathi, R and Selvam, C},
title = {Targeting Poly (ADP-Ribose) Polymerase-1 for the Treatment of Neurodegenerative Diseases.},
journal = {Chemical biology & drug design},
volume = {106},
number = {5},
pages = {e70189},
doi = {10.1111/cbdd.70189},
pmid = {41178110},
issn = {1747-0285},
mesh = {Humans ; *Neurodegenerative Diseases/drug therapy/metabolism/pathology/enzymology ; *Poly (ADP-Ribose) Polymerase-1/metabolism/antagonists & inhibitors ; alpha-Synuclein/metabolism ; Animals ; *Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use/chemistry/pharmacology ; tau Proteins/metabolism ; Amyloid beta-Peptides/metabolism ; },
abstract = {Poly (ADP-ribose) Polymerase 1 (PARP1) has many functions that intertwine with the pathology of many diseases. Because of PARP1's function in DNA repair and cell death, neurodegeneration research is another pathology that PARP1 included. By PARylation, PARP1 acts as a direct and indirect modulator of amyloid β, α-Synuclein (α-syn), tau protein, and other proteins indicated in neurodegenerative diseases. PARylation influences the function, activation, and localization of these proteins. This review paper overviews neurodegeneration and the significant diseases resulting from neurodegeneration and compiles mechanisms and functions Poly (ADP-ribose) Polymerase-1 has in neurodegenerative diseases.},
}

Humans
*Neurodegenerative Diseases/drug therapy/metabolism/pathology/enzymology
*Poly (ADP-Ribose) Polymerase-1/metabolism/antagonists & inhibitors
alpha-Synuclein/metabolism
Animals
*Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use/chemistry/pharmacology
tau Proteins/metabolism
Amyloid beta-Peptides/metabolism

@article {pmid41177743,
year = {2025},
author = {Pereira da Silva, AM and de Deus, O and Ribeiro, FV and Tudella, GCN and Cabeça, LS and Silva, LL and Han, ML and Franco, JO and Costa, JGP and Santos do Nascimento, MDV and Andrade Fernandes, JV and Franco, ES and de Sousa Maia, MB},
title = {Efficacy and Safety of Lithium for Behavioral and Cognitive Symptoms in Alzheimer's Disease Dementia: A Systematic Review With Frequentist and Bayesian Meta-Analysis.},
journal = {The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jagp.2025.10.001},
pmid = {41177743},
issn = {1545-7214},
abstract = {BACKGROUND: Alzheimer's disease (AD) dementia is the leading cause of cognitive decline in late life, yet treatment options remain limited. Lithium, widely used in bipolar disorder, has been suggested to exert neuroprotective effects through inhibition of GSK-3β and modulation of amyloid and tau pathology. We aimed to evaluate the efficacy and safety of lithium in AD dementia.

METHODS: This systematic review and meta-analysis was prospectively registered in PROSPERO and conducted following PRISMA guidelines. We searched PubMed, Embase, and Cochrane Library through April 2025 for randomized controlled trials (RCTs) comparing lithium with placebo or standard therapy in patients with AD dementia or amnestic mild cognitive impairment. Outcomes included cognition (MMSE, ADAS-Cog, memory tasks), function (CDR-SB, conversion to AD), neuropsychiatric symptoms (NPI), CSF biomarkers, and safety (adverse events [AEs], serious AEs [SAEs]). Random-effects meta-analyses were complemented by Bayesian methods and trial sequential analyses.

RESULTS: Six RCTs involving 394 participants (196 lithium, 198 placebo) met inclusion criteria. Lithium did not significantly improve global cognition (MMSE: MD -1.61, 95% CI -4.11 to 0.88; ADAS-Cog: MD -1.82, -3.05 to -0.60; both with high heterogeneity). Memory outcomes were mixed, with possible benefit for figure recall but not delayed verbal recall. No consistent benefits were observed for episodic memory, functional outcomes (CDR-SB), neuropsychiatric symptoms, or CSF biomarkers. Safety analyses showed no increased risk of SAEs; drug-related AEs were more frequent but heterogeneous across trials.

CONCLUSIONS: Lithium demonstrated an acceptable safety profile within the dosing regimens studied. However, current evidence does not support consistent cognitive or functional benefits in AD dementia. Larger, well-designed RCTs are warranted to clarify its potential therapeutic role.},
}

@article {pmid41177416,
year = {2025},
author = {Bashir, B and Gulati, M and Vishwas, S and Hussain, MS and Gupta, G and Kumar, P and Negi, P and Mittal, N and Dua, K and Singh, SK},
title = {Bridging the gap in the management of Alzheimer's disease using fecal microbiota transplantation.},
journal = {Molecular and cellular neurosciences},
volume = {},
number = {},
pages = {104052},
doi = {10.1016/j.mcn.2025.104052},
pmid = {41177416},
issn = {1095-9327},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disease that greatly impairs the health status of human beings and creates significant burdens on individuals, families, and society. AD is characterized by the buildup of pathological proteins and glial cell dysregulated activity. Additional hallmark features include oxidative stress, neuroinflammation, impaired autophagy, cellular senescence, mitochondrial dysfunction, epigenetic alterations, reduced neurogenesis, increased blood-brain barrier permeability, and age-inappropriate intestinal dysbiosis. There is significant evidence that shows that microbiota in the gut affects the development and progression of AD. As a result, gut microbiota modulation has been identified as a new method of clinical management of AD, and more and more efforts have been devoted to identifying new methodologies for its prevention and treatment. This paper will discuss the role of gut microbiome in the etiopathogenesis of AD and consider the possibilities of fecal microbiota extract (FME) supplementation, commonly referred to as fecal microbiota transplantation (FMT). It is both a prophylactic and curative approach. The FMT therapy is grounded on the premise that anti-inflammatory effects, modifications of amyloid β, improved synaptic plasticity, short-chain fatty acids, and histone acetylation are the principles behind the enhancement of AD. The current review will present an overview of the linkage between FMT and AD as well. It further examines and evaluates the effects of FMT on aging-based mechanisms that support the development of AD. It also provides a broad description of the recent clinical and preclinical evidence on the application of FMT to AD.},
}

@article {pmid41177383,
year = {2025},
author = {Gu, T and Ma, S and Liu, W and Wang, L},
title = {Pregnane X receptor activation regulate amyloid transport to improve cognition functions in Alzheimer's disease.},
journal = {European journal of pharmacology},
volume = {1007},
number = {},
pages = {178310},
doi = {10.1016/j.ejphar.2025.178310},
pmid = {41177383},
issn = {1879-0712},
abstract = {OBJECTIVES: To explore the concept about nuclear receptor pregnane X receptor (PXR) activation could be beneficial for the Alzheimer's disease (AD) treatment, as well as the underlying mechanism.

METHODS: For in vitro experiments, human brain microvascular endothelial cells (hCMEC/D3) were exposed to Aβ42 and hyperforin (HPF), a human PXR agonist followed by measurement of P-glycoprotein(P-gp)and low-density lipoprotein receptor-related protein 1 (LRP1) expression. Further, 7 months old 5 × FAD mice were used for in vivo experiments. Due to the species-difference characteristics of PXR, these mice were treated with pregnenolone carbonitrile (PCN, a rodent PXR agonist) rather than hPXR agonist, or corn oil for 28 days. Meanwhile, untreated C57BL/6 mice were used as the control group. The improvements of animal behavior were evaluated by Morris water maze and novel arm exploration test. The pathological profiles were assessed by immunohistochemistry and transmission electron microscopy. The cerebral blood flow (CBF) and Aβ transporters were analyzed by speckle contrast imaging and Western blot respectively.

RESULTS: In vitro experiments showed that the P-gp and LRP1 levels in hCMEC/D3 were reduced due to exposure of Aβ42, while HPF can restore their expression levels. 5 × FAD mice treated with the PCN improved cognitive functions and cerebral blood flow. These functional improvements were associated with a reduction in amyloid plaques, cerebral amyloid angiopathy, neuroinflammation and a recovery of blood-brain barrier transport function. The underlying mechanisms could be that PXR activation up-regulates the expression of P-gp and LRP1 and inhibits inflammation via STAT3, and increases the clearance of Aβ42 in the brain.

CONCLUSIONS: These results demonstrate the beneficial impact of PXR activation on cognitive functions, parenchymal amyloid plagues and cerebral angiopathy, and highlights the therapeutic potential of PXR agonists for treatment of AD patients.},
}

@article {pmid41176545,
year = {2025},
author = {El Hajj, W and Pujo-Menjouet, L and Tine, LM and Volpert, V},
title = {Modelling of anti-inflammatory treatment in the Alzheimer disease: optimal regimen and outcome.},
journal = {Bulletin of mathematical biology},
volume = {87},
number = {12},
pages = {171},
pmid = {41176545},
issn = {1522-9602},
support = {Project-ANR-21-CE15-0011//PrionDiff/ ; },
mesh = {*Alzheimer Disease/drug therapy/immunology ; Humans ; *Anti-Inflammatory Agents, Non-Steroidal/administration & dosage/therapeutic use ; Mathematical Concepts ; Cytokines/metabolism ; *Models, Biological ; Treatment Outcome ; Computer Simulation ; Microglia/drug effects ; Disease Progression ; Inflammation Mediators/metabolism/antagonists & inhibitors ; },
abstract = {The application of non-steroidal anti-inflammatory drugs (NSAIDs) for Alzheimer's disease is considered to be a promising therapeutic approach. Epidemiological studies suggest potential benefits of NSAIDs; however, these findings are not consistently supported by clinical trials. This long-standing discrepancy has persisted for decades and remains a significant barrier to developing effective treatment strategies. To assess the efficacy of NSAIDs in Alzheimer's disease, we have developed a mathematical model based on a system of ordinary differential equations. The model captures the dynamics of key players in disease progression, including A β -monomers, oligomers, pro-inflammatory mediators (M1 microglial cells and pro-inflammatory cytokines), and anti-inflammatory mediators (M2 microglial cells and anti-inflammatory cytokines). The effects of NSAIDs are modeled through a reduction in the production rate of inflammatory cytokines (IC). While a single NSAID administration temporarily reduces IC levels, their concentration eventually returns to baseline due to drug elimination. The return time depends on the drug dose, resulting in a patient-specific return time function. By analyzing this function, we propose an optimal treatment regimen and identify conditions under which NSAID treatment is most effective in reducing IC levels. Our results suggest that NSAID efficacy in Alzheimer's disease is influenced by the stage of the disease (with earlier intervention being more effective), patient-specific parameters, and the treatment regimen. The approach developed here can also be generalized to evaluate the efficacy of anti-inflammatory treatments for other diseases.},
}

*Alzheimer Disease/drug therapy/immunology
Humans
*Anti-Inflammatory Agents, Non-Steroidal/administration & dosage/therapeutic use
Mathematical Concepts
Cytokines/metabolism
*Models, Biological
Treatment Outcome
Computer Simulation
Microglia/drug effects
Disease Progression
Inflammation Mediators/metabolism/antagonists & inhibitors

@article {pmid41175945,
year = {2025},
author = {Fujii, K and Takeuchi, T and Fujino, Y and Tanaka, N and Fujino, N and Takeda, A and Minakawa, EN and Nagai, Y},
title = {Oral administration of arginine suppresses Aβ pathology in animal models of Alzheimer's disease.},
journal = {Neurochemistry international},
volume = {191},
number = {},
pages = {106082},
doi = {10.1016/j.neuint.2025.106082},
pmid = {41175945},
issn = {1872-9754},
abstract = {Although amyloid β (Aβ)-targeting antibody therapies for Alzheimer's disease (AD) have recently been developed, their clinical efficacy remains limited, and issues such as high cost and adverse effects have been raised. Therefore, there is an urgent need for the establishment of safe and cost-effective therapeutic approaches that inhibit Aβ aggregation or prevent its accumulation in the brain. In this study, we report that arginine, a clinically approved and safe chemical chaperone, suppresses Aβ aggregation both in vitro and in vivo. We demonstrated using an in vitro assay that arginine inhibits the aggregation formation of the Aβ42 peptide in a concentration-dependent manner. In a Drosophila model of AD expressing the Aβ42 peptide with an Arctic mutation E22G, the oral administration of arginine dose-dependently reduced Aβ42 accumulation and rescued Aβ42-mediated toxicity. In an App[NL-G-F] knockin mouse model harboring human APP familial mutations, the oral administration of arginine suppressed Aβ plaque deposition and reduced the level of insoluble Aβ42 in the brain. The arginine-treated App[NL-G-F] knockin mice also showed the improvement of behavioral abnormalities and the reduced expression of the neuroinflammation-associated cytokine genes. These results indicate that the oral administration of arginine not only reduced Aβ deposition, but also ameliorated Aβ-mediated neurological phenotypes in animal models of AD. These findings identify arginine as a safe and cost-effective drug candidate that suppresses Aβ aggregation, and highlight its repositioning potential for rapid clinical translation for AD treatment. Arginine is also potentially applicable to a wide range of neurodegenerative diseases caused by protein misfolding and aggregation.},
}

@article {pmid41175916,
year = {2025},
author = {Vanya, and Kumari, S and Bagri, K and Deshmukh, R},
title = {Tangles and Plaques: A deep dive into the pathological hallmarks of Alzheimer's disease.},
journal = {Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuroscience.2025.10.050},
pmid = {41175916},
issn = {1873-7544},
abstract = {Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder. In AD, there is a gradual impairment of memory and cognitive function that interferes with daily living. The pathophysiology of AD revolves around complex interactions between amyloid-β (Aβ) overproduction and accumulation, followed by tau hyperphosphorylation, which together promote a cascade of neuronal dysfunction and degeneration. AD has two forms, sporadic and familial, with genetic variants such as triggering receptor expressed on myeloid cells-2 (TREM2). Various other variants also lead to impaired amyloid clearance and altered immune responses. Along with these genetic factors, aging remains the primary risk factor, and environmental as well as lifestyle factors can act synergistically to accelerate disease onset and progression. Although significant advances have been made in the last five decades, there has been only limited progress in the treatment because of a poor understanding of the molecular basis of AD. This makes current treatments largely focus on symptomatic management. This narrative review provides an updated synthesis of Alzheimer's disease pathophysiology, focusing on Aβ and tau pathology, glial activation, neuroinflammatory cascades, disrupted neurogenesis, and blood-brain barrier dysfunction. A focus and deeper understanding can help to develop new strategies that might work beyond the present conventional treatment. Due to the increasing global prevalence of AD, it is important to continue research into these mechanisms for the development of more effective interventions and improved patient outcomes.},
}

@article {pmid41175892,
year = {2025},
author = {Prajapati, P and Desai, A and Shah, P and Pulusu, V and Haque, A and Kalam, MA and Shah, S},
title = {Comparative in-vivo and in-vitro characterization of Donepezil loaded Lactoferrin linked PEG coated and uncoated nanocarriers as intranasal drug delivery system.},
journal = {Journal of liposome research},
volume = {},
number = {},
pages = {1-17},
doi = {10.1080/08982104.2025.2573681},
pmid = {41175892},
issn = {1532-2394},
abstract = {Alzheimer's disease treatment faces challenges with conventional oral formulations of donepezil (DNP). This study aims to develop and characterize DNP-loaded Lactoferrin (LCF)-linked PEG-coated nano-carriers for intranasal delivery. The formulation was developed using a Quality by Design (QbD) approach integrated with molecular docking. A novel micelle-enhanced spectrofluorimetric method was developed and validated for in-vitro and in-vivo characterization of the nano-carriers. The method was optimized using Analytical Quality by Design (AQbD) principles. In-vivo pharmacokinetic and bio-distribution studies were conducted in rats to compare the developed formulation with uncoated NLCs and conventional dosage forms. The LCF-PEG-coated NLCs showed improved brain targeting efficiency compared to uncoated NLCs and conventional formulations. The spectrofluorimetric method demonstrated high sensitivity and reliability for both in-vitro and in-vivo analyses. The developed DNP-loaded LCF-PEG-coated NLCs show promise as an effective intranasal delivery system for Alzheimer's disease treatment. The novel spectrofluorimetric method offers a sustainable and efficient alternative to conventional LC-MS/MS techniques for characterizing DNP formulations.},
}

@article {pmid41175671,
year = {2025},
author = {Träuble, J and Hiscox, LV and Johnson, CL and Aviles-Rivero, A and Schönlieb, CB and Kaminski Schierle, GS},
title = {Brain age prediction and early neurodegeneration detection using contrastive learning on brain biomechanics: a retrospective, multicentre study.},
journal = {EBioMedicine},
volume = {121},
number = {},
pages = {105996},
doi = {10.1016/j.ebiom.2025.105996},
pmid = {41175671},
issn = {2352-3964},
abstract = {BACKGROUND: One of the main reasons why drugs for neurodegenerative diseases often fail is that treatment typically begins only after symptoms have appeared-by which point significant, and possibly irreversible, damage may have already occurred. Non-invasive imaging techniques, such as Magnetic Resonance Imaging (MRI), have previously been explored for presymptomatic diagnosis, but with limited success. More recently, Magnetic Resonance Elastography (MRE)-a technique capable of mapping the brain's biomechanical properties, including stiffness and damping ratio-has shown promise in detecting early changes. However, current studies have been limited by small sample sizes, and a lack of robust algorithms capable of accurately interpreting data under such constraints.

METHODS: We developed a self-supervised contrastive regression framework trained on 3D MRE-derived stiffness and damping ratio maps from 311 healthy individuals (aged 14-90) and evaluated its performance against structural 3D T1-weighted MRI. Brain age predictions were used to compute brain age gaps (BAGs), quantifying deviations from normative ageing trajectories. We applied the models to Alzheimer's disease (AD, n = 11) and mild cognitive impairment (MCI, n = 20) cohorts, and analysed whole-brain and region-specific predictions using occlusion-based saliency maps and subcortical segmentation.

FINDINGS: Self-supervised models using MRE achieved a mean absolute error (MAE) of 3.51 years in brain age prediction-significantly outperforming MRI (MAE: 4.79 years, p < 0.05) under matched conditions. The greater age sensitivity of MRE translated into improved differentiation of Alzheimer's disease (AD) and mild cognitive impairment (MCI) from healthy individuals. Stiffness was the dominant ageing biomarker in AD (BAG increase: +9.2 years, p < 0.05), whereas damping ratio revealed early MCI-related changes (BAG increase: +6.3 years, p < 0.05). Region-wise analysis identified the caudate (stiffness) and thalamus (damping ratio) as key markers for AD and MCI, respectively. Notably, some cognitively normal individuals exhibited biomechanical profiles resembling patients with MCI or AD, suggesting that these individuals may share some biomechanical characteristics with clinical populations.

INTERPRETATION: In our controlled experimental setting, MRE combined with contrastive learning provides a sensitive, non-invasive biomarker of brain ageing and neurodegeneration, outperforming MRI and differentiating disease stage-specific biomechanical signatures. Regional BAG profiling may have the potential to identify at-risk, cognitively normal individuals, which could facilitate timely intervention trials in the future, pending longitudinal validation.

FUNDING: Gates Cambridge Trust; Cambridge Centre for Data-Driven Discovery (Schmidt Sciences); Wellcome Trust; NIH (R01-AG058853, U01-NS112120); UK EPSRC; UK MRC; Alzheimer's Research UK; Michael J. Fox Foundation; Infinitus China Ltd.},
}

@article {pmid41175292,
year = {2025},
author = {Pennington, B and Davis, S and Cranmer, H},
title = {Caring for and Caring about in Economic Evaluation: Modelling the Family and Caregiving Effects.},
journal = {PharmacoEconomics},
volume = {},
number = {},
pages = {},
pmid = {41175292},
issn = {1179-2027},
support = {NIHR300160//NIHR/ ; },
abstract = {Current methods for modelling spillover effects on carers in economic evaluation include four main methods: (absolute) utilities, disutilities, increments and multipliers. Each of these approaches assumes that the spillover effect is one-dimensional. We aimed to develop a new approach that better reflects the complexity of caring and the nuances of how a new treatment may impact the caregiver. We propose a new method based on the established concepts of the 'family effect' (or caring about someone) and the 'caregiving effect' (providing care for someone). These effects can be disentangled through analysis of carer-patient dyads or using patient and carer (dis)utilities and estimates from the literature. We consider case studies in Duchenne Muscular Dystrophy, Spinal Muscular Atrophy and Alzheimer's Disease. Our approach models a small carer health-related quality of life (HRQoL) gain for each intervention, whereas the utility approach consistently models a substantial carer HRQoL gain, and the disutility approach models a carer HRQoL loss in two case studies. Our method allows explicit consideration of the benefits to carers of extending patient survival or improving patient health, with the negative HRQoL impact of increased caregiving burden. We propose that our method can be used with published data at present, and further research should analyse the family and caregiving effects in different conditions.},
}

@article {pmid41174898,
year = {2025},
author = {Wang, C and Guo, R and Wang, X and Li, H and Zhong, T},
title = {Post-Translational Modifications of Tubulin in Oocyte Maturation and Female Infertility.},
journal = {Cytoskeleton (Hoboken, N.J.)},
volume = {},
number = {},
pages = {},
doi = {10.1002/cm.70062},
pmid = {41174898},
issn = {1949-3592},
support = {82101864//National Natural Science Foundation of China/ ; ZR2025MS508//Natural Science Foundation of Shandong Province/ ; 2023KJ262//Shandong Provincial Youth Innovation Technology Support Program/ ; 2023YXNS228//Key R&D Plan of Jining City/ ; 2023-1-43//Ji'nan Municipal Health Commission Science and Technology Plan Project/ ; 202412//High-Level Talents in the Medical and Health Industry in Ji'nan/ ; },
abstract = {Microtubules are critical components of the cytoskeleton that are extensively involved in various cellular and biological processes. The execution of these functions is intricately linked to post-translational modifications of tubulin. Post-translational modifications of tubulin include acetylation, tyrosination, de-tyrosination, glutamylation, SUMOylation, and so on. These modifications are closely associated with a wide range of biological processes. Accumulating evidence indicates that aberrant microtubule modifications are implicated in various diseases, including cancer, Alzheimer's disease, neurodevelopmental disorders, cardiac atrial hypertrophy, and even infertility. Aneuploid oocytes are a common cause of infertility, spontaneous abortion, trisomy syndrome, and other congenital abnormalities. The occurrence of aneuploidy is often closely associated with defects in spindle assembly, which are influenced by a series of tubulin modifications. In this review, we aimed to summarize the factors that affect tubulin modification and explore the key mechanisms underlying aneuploidy in human oocytes, thereby providing new insights and strategies for the treatment of infertility and prevention of congenital defects in newborns.},
}

@article {pmid41174000,
year = {2025},
author = {Zhao, Q and Gou, C and Luo, G and Dai, S and Wang, D and Zhang, S and Wang, F and Xu, H and Han, Y and Wang, S},
title = {Combined multi-omics and brain pathology reveal novel biomarkers for alzheimer's disease.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {38239},
pmid = {41174000},
issn = {2045-2322},
support = {81260199, 81660228, and 82160261//National Natural Science Foundation of China/ ; L-2019019//Yunnan Province Talent Training Program/ ; RLMY20200005//Yunnan High-Level Talent Training Support Program Famous Doctor Special Project/ ; 202303AC100026//Yunnan Province Key Research and Development Program/ ; 202401AY070001-008//Kunming Medical University Joint Special Key Project/ ; },
mesh = {*Alzheimer Disease/pathology/metabolism/genetics ; Animals ; *Biomarkers/metabolism ; Mice ; Proteomics/methods ; Protein Interaction Maps ; *Hippocampus/metabolism/pathology ; Transcriptome ; Gene Expression Profiling ; *Brain/pathology/metabolism ; Disease Models, Animal ; Mice, Transgenic ; Amyloid beta-Protein Precursor/genetics/metabolism ; Multiomics ; },
abstract = {Alzheimer's disease (AD) is a complex disorder with significant genetic contributions, yet only a limited number of risk loci have been conclusively identified. This research aimed to discover novel potential biomarkers for AD through multi-omics and brain pathology analysis. In this study, we investigated hippocampal molecular alterations in APP/PS1 mouse using transcriptomics and data-independent acquisition (DIA) proteomics. To further validate the involvement of differentially expressed genes (DEGs) and differentially expressed proteins (DEPs) in AD pathology and potential drug treatment, we performed an integrative analysis incorporating pathological data and protein-protein interaction networks. We identified 263 DEGs and 448 DEPs. Integrative transcriptomic and proteomic analyses revealed five co-upregulated DEGs/DEPs and one co-downregulated DEG/DEP. Comparison of KEGG pathway enrichment between the two datasets showed significant involvement in the complement and coagulation cascade, as well as neurodegeneration-multiple diseases. Furthermore, mRNA levels of LY86, CD180, and C1QB were strongly associated with amyloid-β plaque load in the AD mouse hippocampus. Protein-protein interaction analysis suggested that APP, LY86, CD180, and C1QB could serve as potential therapeutic targets for AD. The study identified three novel AD loci (EGFL8, ERMN, and CD180), with CD180 showing association with AD at both the expression and pathological levels, highlighting their potential roles in disease progression and therapeutic intervention.},
}

*Alzheimer Disease/pathology/metabolism/genetics
Animals
*Biomarkers/metabolism
Mice
Proteomics/methods
Protein Interaction Maps
*Hippocampus/metabolism/pathology
Transcriptome
Gene Expression Profiling
*Brain/pathology/metabolism
Disease Models, Animal
Mice, Transgenic
Amyloid beta-Protein Precursor/genetics/metabolism
Multiomics

@article {pmid41173323,
year = {2025},
author = {Morrow, CB and Sah, E and Onyike, CU},
title = {Examining neuropsychiatric symptoms and functional decline in behavioral variant frontotemporal dementia.},
journal = {International review of psychiatry (Abingdon, England)},
volume = {},
number = {},
pages = {1-9},
doi = {10.1080/09540261.2025.2571072},
pmid = {41173323},
issn = {1369-1627},
abstract = {AIM: Neuropsychiatric symptoms (NPS) are core features of behavioral variant frontotemporal dementia (bvFTD), but their association with functional decline is incompletely understood.

METHODS: Participants (N = 219) were individuals enrolled in Alzheimer's Disease Research Centers between 2005 and 2024 with early-stage bvFTD (CDR ≤ 0.5). Functional status was coded as a binary variable based on the Functional Activities Questionnaire. Behavioral data were derived from the Neuropsychiatric Inventory Questionnaire and Clinician Judgement of Symptoms. Descriptive statistics and Cox proportional hazard analyses were used to characterize functional impairments and their association with NPS.

RESULTS: Impairments in transactions (47%) and verbal communication (44%) were common at baseline, while impairments in self-care and incontinence (<10%) were rare. Apathy (65%), disinhibition (55%), depression, anxiety, irritability, and agitation were common at baseline (>40%). Psychosis was rare at baseline (<10%). By visit 4, impairments in transactions (81%), meal-preparation (65%), self-care (55%) and verbal communication (61%) were common. Emergence of apathy, disinhibition, depression, anxiety, and irritability were associated with an increased hazard of impairments in ambulation, meal preparation, self-care, and transactions.

CONCLUSION: NPS in bvFTD are frequent, occur early, and are associated with functional decline. Timely recognition and treatment of NPS may mitigate their impact on function.},
}

@article {pmid41173224,
year = {2025},
author = {Zheng, M and Zhang, Q and Siebert, HC and Loers, G and Wen, M and Wang, Q and Zhang, R and Han, J and Zhang, N},
title = {Semaglutide attenuates Alzheimer's disease model progression by targeting microglial NLRP3 inflammasome-mediated neuroinflammation and ferroptosis.},
journal = {Experimental neurology},
volume = {},
number = {},
pages = {115537},
doi = {10.1016/j.expneurol.2025.115537},
pmid = {41173224},
issn = {1090-2430},
abstract = {Microglial activation driven by NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome signaling exacerbates Alzheimer's disease (AD) pathology through enhanced neuroinflammation and amyloid beta (Aβ) accumulation. Semaglutide (SEM) has attracted growing attention for its potential therapeutic effects in AD, while its underlying mechanisms remain unclear. In this study, we investigated the neuroprotective effects of SEM in both APP/PS1 transgenic mice and LPS + ATP-stimulated BV2 microglia. Our results demonstrate that SEM treatment rescued APP/PS1 mice from cognitive impairment and suppressed Aβ aggregation and tau hyper-phosphorylation in the hippocampus of APP/PS1 mice. Furthermore, we found that SEM inhibited microglial NLRP3 activation, promoted microglial M2 polarization and alleviated ferroptosis via NLRP3/nuclear factor kappa B (NF-κB) and nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase 1 (HO-1)/ cystine/glutamate antiporter SLC7A11 (xCT)/glutathione peroxidase 4 (GPX4) pathways in APP/PS1 mice and LPS + ATP-stimulated BV2 microglia. These findings were further corroborated by microglia-specific NLRP3 knockdown, which reduced Aβ deposition, promotied M2 polarization, attenuated neuroinflammation, and suppressed ferroptosis. Our findings provide further theoretical support for the clinical application of SEM in AD treatment, while also establishing a scientific foundation for AD therapeutic strategies targeting the microglial NLRP3 pathway.},
}

@article {pmid41172319,
year = {2025},
author = {Avdeenko, TA and Guseinova, NM and Dzhafarzade, FY and Zagorul'ko, AA},
title = {[Modern therapeutic strategies for the treatment of Alzheimer's disease (literature review).].},
journal = {Advances in gerontology = Uspekhi gerontologii},
volume = {38},
number = {3},
pages = {441-449},
pmid = {41172319},
issn = {1561-9125},
mesh = {*Alzheimer Disease/therapy/drug therapy/metabolism ; Humans ; *Cholinesterase Inhibitors/therapeutic use ; Amyloid beta-Peptides/metabolism ; *Diabetes Mellitus, Type 2/complications/drug therapy/metabolism ; Immunotherapy/methods ; tau Proteins/metabolism ; Calcium Channel Blockers/therapeutic use ; Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors ; },
abstract = {The article analyzes contemporary literature data on standard and alternative therapeutic methods for Alzheimer's disease (AD). The main approaches currently include the use of cholinesterase inhibitors and NMDA receptor antagonists, which help slow disease progression and improve patients' quality of life. Due to their insufficient effectiveness, there is a search for new treatment methods based on the connection between AD and other conditions. This article will examine the cross-mechanisms of pathogenesis linking type 2 diabetes and AD, as well as analyze new therapeutic approaches, including intranasal insulin administration and the use of insulin sensitizers. Neurodegenerative processes, including AD, are based on a violation of intracellular calcium metabolism, which suggested the potential efficiency of calcium channel blocker drugs currently used in the treatment of arterial hypertension. Key hypotheses regarding the pathogenesis of AD include the amyloid hypothesis, based on the accumulation of beta-amyloid, and the tau hypothesis, related to hyperphosphorylated tau protein aggregation. Alternative mechanisms such as neuroinflammation are also discussed. In this context, an innovative method for treating AD is immunotherapy, aimed at eliminating beta-amyloid that causes neurodegeneration. Thus, the necessity for integrating various hypotheses for a more comprehensive understanding of pathology and developing effective therapeutic strategies is emphasized. The article highlights the importance of further research in this field.},
}

*Alzheimer Disease/therapy/drug therapy/metabolism
Humans
*Cholinesterase Inhibitors/therapeutic use
Amyloid beta-Peptides/metabolism
*Diabetes Mellitus, Type 2/complications/drug therapy/metabolism
Immunotherapy/methods
tau Proteins/metabolism
Calcium Channel Blockers/therapeutic use
Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors

@article {pmid41170731,
year = {2026},
author = {Duan, T and Mao, H and Jiang, X and Tian, Y and Zhang, J and Tan, J},
title = {Harnessing copper: Innovative approaches to combat neurodegenerative diseases and cancer (Review).},
journal = {International journal of molecular medicine},
volume = {57},
number = {1},
pages = {},
doi = {10.3892/ijmm.2025.5678},
pmid = {41170731},
issn = {1791-244X},
mesh = {Humans ; *Copper/metabolism ; *Neurodegenerative Diseases/metabolism/drug therapy ; *Neoplasms/metabolism/drug therapy ; Animals ; Chelating Agents/therapeutic use ; },
abstract = {Copper is an important trace element in the human body and plays an essential role in cells, where it is involved in synthesizing copper‑dependent enzymes, including superoxide dismutase, cytochrome c oxidase, tyrosinase, lysyl oxidase, dopamine‑β‑hydroxylase and other related copper‑containing enzymes. Copper overload or deficiency affects cell activity, leading to the development of neurodegenerative diseases or cancer. Neurodegenerative diseases, including Alzheimer's, Parkinson's and Huntington's disease, as well as cancer, represent significant chronic health burdens. The complexity of their pathophysiological mechanisms, coupled with the limitations of current targeted therapies, complicates the development of effective treatments. This review provides a comprehensive overview of the current understanding of copper's regulatory mechanisms in health and disease, with particular emphasis on its roles in neurodegenerative disorders and cancer. Recent advances in copper‑targeted therapeutic strategies, including copper chelators, ionophores and copper‑based nanoparticles, were highlighted. Furthermore, the clinical potential, key challenges and future prospects of these interventions were assessed. By synthesizing recent preclinical and clinical evidence, this review aims to contribute novel perspectives for improving the treatment of copper‑associated diseases.},
}

Humans
*Copper/metabolism
*Neurodegenerative Diseases/metabolism/drug therapy
*Neoplasms/metabolism/drug therapy
Animals
Chelating Agents/therapeutic use

@article {pmid41170545,
year = {2025},
author = {Li, XJ and Zheng, B and Lan, P and Zhang, WX and Li, YP and He, Z},
title = {[Research progress in the role of HCN channels in Alzheimer's disease].},
journal = {Sheng li xue bao : [Acta physiologica Sinica]},
volume = {77},
number = {5},
pages = {867-875},
doi = {10.13294/j.aps.2025.0078},
pmid = {41170545},
issn = {0371-0874},
mesh = {Humans ; *Alzheimer Disease/physiopathology ; *Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels/physiology ; Animals ; Amyloid beta-Peptides/metabolism ; },
abstract = {Alzheimer's disease (AD) is the commonest neurodegenerative disease that causes memory decline, cognitive dysfunction and behavior disorders in the aged people. Primary pathological hallmarks of AD include amyloid-β (Aβ), neurofibrillary tangles (NFTs), gliosis, and neuronal loss. Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels have important physiological functions, especially in aspects of controlling the resting membrane potential, pacemaker activity, memory formation, sleep and arousal. This article reviews the structure, distribution, regulation of HCN channels and the role of HCN channels in the pathological mechanisms of AD, aiming to provide drug therapeutic targets for the prevention and treatment of AD.},
}

Humans
*Alzheimer Disease/physiopathology
*Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels/physiology
Animals
Amyloid beta-Peptides/metabolism

@article {pmid41170438,
year = {2025},
author = {Zhang, X and Huang, X and Chang, M},
title = {Association between periodontal disease and Alzheimer's disease: a scoping review.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1588008},
pmid = {41170438},
issn = {1663-4365},
abstract = {BACKGROUND: Alzheimer's disease (AD) is the most common type of dementia, with mild cognitive impairment (MCI) as its early reversible stage. Periodontal disease (PD) is a chronic inflammatory condition associated with systemic diseases. Recent studies suggest a potential link between PD and AD/MCI. This scoping review evaluates the existing evidence on the association between PD and AD and explores possible mechanisms.

METHODS: A literature search was conducted in PubMed, Embase, and Cochrane databases (September 2025), covering studies from 2004 to 2025. Human clinical studies, animal models, and in vitro experiments were included, while reviews were excluded. Two independent researchers performed study selection, data extraction, and quality assessment.

RESULTS: A total of 52 studies were included after screening 1,369 records. Among them, 25 clinical studies examined the PD-AD association, including case-control, cohort, and cross-sectional studies. Additionally, 24 studies investigated underlying mechanisms, and 3 animal studies assessed PD-related interventions for AD. Evidence suggests PD increases the risk of AD and accelerates cognitive decline. Potential mechanisms include amyloid-β (Aβ) and tau protein aggregation, neuroinflammation triggered by Porphyromonas gingivalis (Pg) infection, and gut-brain axis dysregulation. Periodontal treatment and probiotics may have protective effects against AD-related pathology.

CONCLUSIONS: PD may be a modifiable risk factor for AD, and periodontal interventions could contribute to AD prevention and management. Further clinical studies are needed to confirm the therapeutic potential of targeting oral microbiota in AD.},
}

@article {pmid41170189,
year = {2025},
author = {Pakdel, M and Asle-Rousta, M and Sadegh, M and Eidi, A},
title = {Linalool vs linalool-loaded chitosan nanoparticles in an Aβ-induced rat model of Alzheimer's disease: A molecular, biochemical, histological, and behavioral study.},
journal = {Iranian journal of basic medical sciences},
volume = {28},
number = {11},
pages = {1495-1504},
pmid = {41170189},
issn = {2008-3866},
abstract = {OBJECTIVES: Recent studies have increasingly focused on applying nanotechnology to treat neurodegenerative diseases. In this study, we compared the effects of the monoterpene linalool and linalool-loaded chitosan nanoparticles on key pathological features of Alzheimer's disease (AD), including oxidative stress, neuroinflammation, neuronal death, amyloid plaque deposition, alterations in tryptophan metabolism, and memory deficit in a rat model of AD.

MATERIALS AND METHODS: An intracerebroventricular injection of Aβ42 (10 µg) was used to induce the AD model. Linalool (25 mg/kg) and nano-linalool (25 mg/kg) were administered orally once daily for 30 consecutive days.

RESULTS: Both linalool and nano-linalool significantly reduced malondialdehyde levels and enhanced superoxide dismutase activity in the hippocampus. They also decreased the mRNA levels of monocyte chemoattractant protein-1, inhibited the up-regulation of beta-secretase, reduced amyloid plaque deposition, and attenuated pyramidal neuron death in the CA1 region. Additionally, treatment with both compounds down-regulated indoleamine 2,3-dioxygenase, lowered kynurenine levels, and increased serotonin concentrations in the hippocampus. Although both treatments improved learning and spatial memory in Aβ-injected rats, nano-linalool's effectiveness was more significant than that of linalool in modulating the molecular, biochemical, and histological parameters.

CONCLUSION: Encapsulating linalool in chitosan nanoparticles enhances its effectiveness in improving molecular, biochemical, and histological changes in the hippocampus of rat models of AD.},
}

@article {pmid41169672,
year = {2025},
author = {Teipel, S and Baena, A and He, B and Martinez, L and Aguillon, D and Quiroz, YT and Grazia, A},
title = {Thalamus not basal forebrain is atrophied in non-demented PSEN1 E280A carriers.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {17},
number = {4},
pages = {e70206},
pmid = {41169672},
issn = {2352-8729},
abstract = {INTRODUCTION: A previous study of non-demented presenilin-1 (PSEN1) E280A carriers found basal forebrain and hippocampus, but not the thalamus, to be preserved. This study tested the hypothesis of preservation in an independent PSEN1 E280A sample and explored associations with amyloid and tau pathology.

METHODS: We analyzed multimodal neuroimaging data from 57 individuals in the Colombia-Boston (COLBOS) cohort (non-carriers: 30 and carriers: 27). We used Bayesian multiple regression with priors to test our hypothesis.

RESULTS: Carrier status had no effect on basal forebrain (Bayes factor [BF10] = 0.54) and hippocampal volume (BF10 = 1.05). However, smaller volumes were found in the thalamus of mutation carriers (BF10 = 8.74). We found evidence against an effect of amyloid and tau pathology on basal forebrain, but evidence for an effect on the thalamus.

DISCUSSION: Our results support the preservation of the cholinergic basal forebrain and hippocampus, while highlighting early thalamic involvement in PSEN1 E280A carriers. This has implications for future selection of treatment targets.

HIGHLIGHTS: Basal forebrain volume preserved in non-demented presenilin-1 (PSEN1) E280A carriers.Hippocampal volume preserved in non-demented PSEN1 E280A carriers.Thalamic atrophy observed in non-demented PSEN1 E280A carriers.No link between amyloid/tau pathology and basal forebrain volume.Tau burden linked to hippocampal and thalamic volume loss.},
}

@article {pmid41169223,
year = {2025},
author = {Chen, Z and Wang, X and Wang, S and Wu, Z and Wang, H and Chiu, K and Zheng, X and So, KF},
title = {Lycium barbarum glycopeptide protects neurons from amyloid-beta toxicity.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRR-D-25-00501},
pmid = {41169223},
issn = {1673-5374},
abstract = {Oligomeric amyloid-beta deposition within neurons and its associated neurotoxicity are among the most direct indicators of the onset of Alzheimer's disease. Investigations into strategies aimed at reducing amyloid-beta accumulation or promoting its clearance in neurons are currently being carried out. Lycium barbarum glycopeptide is rich in biologically active compounds and possesses antioxidant, anti-inflammatory, and neuroprotective properties. This study verified that the oligomer amyloid-beta1-42 induced toxic effects in mouse N2a neuroblastoma cells, resulting in elevated levels of reactive oxygen species and increased expression of the inflammatory enzyme inducible nitric oxide synthase. Lycium barbarum glycopeptide counteracted these effects by alleviating cell damage, enhancing cell viability, reducing the levels of reactive oxygen species and inducible nitric oxide synthase expression, and up-regulating the mRNA levels of antioxidant enzymes, including superoxide dismutase 1, superoxide dismutase 2, and glutathione peroxidase 4. Lycium barbarum glycopeptide also activated the phosphoinositide 3-kinase/Akt/p70S6K signaling pathway and promoted the expression of brain-derived neurotrophic factor, thus exerting neuroprotective effects. These findings indicate that Lycium barbarum glycopeptide may be a promising candidate for the treatment of Alzheimer's disease.},
}

@article {pmid41169221,
year = {2025},
author = {Zhang, Z and Deng, W and Hu, L and Hu, Y and Zhang, S and Xiong, Y and Liu, X and Yu, P and Yu, S and Yuan, L and Zhang, J},
title = {Zinc homeostasis imbalance: Potential therapeutic value in neurodegenerative diseases.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRR-D-25-00632},
pmid = {41169221},
issn = {1673-5374},
abstract = {Zinc homeostasis genes are a general term for a family of genes responsible for regulating the concentration of intracellular and extracellular zinc ions, including the SLC39 (ZIP) family, the SLC30 (ZnT) family, and the metallothionein family. As an essential trace element, zinc is involved in biomolecular synthesis, energy metabolism, redox regulation, and gene expression. Recent studies have shown that abnormal expression of zinc homeostasis genes mediates neuronal apoptosis through multiple pathways, including oxidative stress and neuroinflammation. Imbalance in zinc homeostasis can result in the pathological development of various neurodegenerative disorders, including the deposition of amyloid-β in Alzheimer's disease and the aberrant aggregation of α-synuclein in Parkinson's disease. Therefore, regulating the expression of zinc homeostasis genes to restore normal zinc levels in vivo may be an effective strategy for treating neurodegenerative diseases. This review comprehensively summarizes the current status of research exploring zinc homeostasis genes across various family subtypes, as well as the altered expression of these genes in different neurodegenerative diseases and the underlying mechanisms. Finally, we propose zinc chelator supplementation as a novel interventional therapy for neurodegenerative diseases. This proposal includes an evaluation of the feasibility, safety, and limitations of this treatment, providing an innovative perspective for the clinical management of neurodegenerative diseases in the future.},
}

@article {pmid41169131,
year = {2025},
author = {Mikellides, G and Emam Jomeh, AA and Roy, EA and Kyriazis, M},
title = {Repetitive Transcranial Magnetic Stimulation in Dementia.},
journal = {Current aging science},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118746098392580251003064940},
pmid = {41169131},
issn = {1874-6128},
abstract = {Repetitive Transcranial Magnetic Stimulation (rTMS) is a non-invasive neuromodulatory technique that is increasingly being investigated for its therapeutic potential in cognitive impairment associated with dementia and Alzheimer's disease. This narrative review synthesizes and critically appraises the current evidence surrounding rTMS, with particular focus on clinical efficacy, neurobiological mechanisms, and emerging innovations. High-frequency stimulation over the Dorsolateral Prefrontal Cortex (DLPFC) has consistently demonstrated improvements in memory, executive function, and attention, likely mediated by enhanced synaptic plasticity, increased neurotrophic factor expression, and modulation of large-scale brain networks, such as the default mode and fronto-parietal networks. Recent high-quality studies have built upon earlier research to highlight the comparative efficacy of target-specific stimulation, including precuneus- and parietal-based protocols, as well as multi- site strategies that engage language and associative regions. It also examines the use of TMSEEG and DMN connectivity as predictors of treatment response, supporting a shift toward personalized, biomarker-guided rTMS paradigms. Moreover, the synergistic potential of combining rTMS with cognitive training and pharmacotherapy is explored as a promising avenue for multimodal treatment. While preliminary results are encouraging, heterogeneity in study design and stimulation parameters continues to limit the generalizability of the findings. Standardization of protocols, longterm efficacy validation, and large-scale clinical trials remain critical to translating rTMS into routine dementia care.},
}

@article {pmid41168999,
year = {2025},
author = {Zhang, J and He, Y and Yang, P and Zhang, H and Tong, Y and Jiang, L and Li, Z and Yan, M and Li, X and Yang, Q and Yang, J and Yuan, Z and Zhang, J and Cheng, J},
title = {Microglial Rack1 Deficiency Alleviates Alzheimer's Disease Pathology through Enhancing IGF1-Mediated Astrocytic Phagocytosis.},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
volume = {},
number = {},
pages = {e15877},
doi = {10.1002/advs.202515877},
pmid = {41168999},
issn = {2198-3844},
support = {82071218//National Nature Science Foundation of China/ ; 82271237//National Nature Science Foundation of China/ ; 81930029//National Nature Science Foundation of China/ ; },
abstract = {Alzheimer's disease (AD) is the most common neurodegenerative disorder. Microglia make significant contributions to neuroinflammation and the progression of AD. However, the regulatory role of microglial activation and the communication between microglia and astrocytes in AD are largely unknown. Here, it is found that Rack1 levels are elevated in microglia of patients with AD and AD model mice. The conditional knockout of Rack1 in microglia reduced Aβ aggregation, alleviated neuroinflammation, and rescued cognitive impairments in AD model mice. Mechanistically, the knockout of Rack1 in microglia decreased the number of microglia while increasing both the numbers and phagocytic activities of astrocytes by upregulating the levels of IGF1. The inhibition of IGF1R blocked microglial Rack1 deficiency-induced astrocyte proliferation and astrocyte-mediated phagocytosis both in vitro and in vivo. Collectively, the results demonstrated that microglial Rack1 contributes to AD pathology, at least partially through influencing IGF1-IGF1R signaling between microglia and astrocytes, thus providing a potential target for AD treatment.},
}

@article {pmid41167569,
year = {2025},
author = {Xiong, R and Liu, H and Zhang, S and Wang, L and Zhang, P and Wang, Y and Ou, X and Wu, A and Lai, X},
title = {Acorus tatarinowii Schott Attenuates Alzheimer's Disease via Neuronal Ferroptosis Inhibition:A Synergistic Network Pharmacology and Multi-Omics Profiling Study.},
journal = {Journal of ethnopharmacology},
volume = {},
number = {},
pages = {120829},
doi = {10.1016/j.jep.2025.120829},
pmid = {41167569},
issn = {1872-7573},
abstract = {The dried rhizome of Acorus tatarinowii Schott (ATR) is the most widely used traditional Chinese medicine for the treatment of dementia due to its effect of opening orifices and eliminating phlegm (Kai-Qiao-Huo-Tan in Chinese), reviving the mind and enhancing intelligence (Xing-Shen-Yi-Zhi in Chinese), but its mechanism remains not fully understood.

AIM OF THE STUDY: To reveal the mechanism of ATR in the treatment of Alzheimer's disease (AD), which is a major type of dementia.

MATERIALS AND METHODS: The effects of ATR on cognitive function and neuronal loss in APP/PS1 mice were evaluated by novel object recognition test, nesting test, hematoxylin-eosin staining and Nissl staining. The underlying mechanism were studied by serum metabolomics, transcriptomics, network pharmacology, RT-PCR, Western blot, immunofluorescence and immunohistochemistry.

RESULTS: ATR significantly improved cognitive function, neuronal loss, and altered lipid metabolism in APP/PS1 mice. In β-amyloid (Aβ)1-42 and ferric citrate (FC)-induced HT22 cells, ATR significantly improved the cell viability, reduced the intracellular free iron, reactive oxygen species and lipid peroxidation, and transcriptome analysis showed that the mechanism was related to ferroptosis and iron metabolism. Network pharmacology analysis indicated that ATR may regulate Nrf2 signaling. Both in vitro and in vivo results showed that ATR increased the mRNA and protein expression of Nrf2 and GPX4. ATR also reduced brain iron deposition, downregulated TFR1 and upregulated FPN1 expression in APP/PS1 mice.

CONCLUSIONS: ATR ameliorated AD by improving iron metabolism and inhibiting neuronal ferroptosis through activation of Nrf2/GPX4 axis, which provided modern medical evidence for the use of ATR to improve AD.},
}

@article {pmid41166911,
year = {2025},
author = {Barth, SW and Efferth, T},
title = {Network pharmacology to elucidate the role of phytotherapy in neurocognitive disorders.},
journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology},
volume = {148},
number = {},
pages = {157031},
doi = {10.1016/j.phymed.2025.157031},
pmid = {41166911},
issn = {1618-095X},
abstract = {BACKGROUND: To date, there are no entirely satisfactory drugs available to treat neurocognitive disorders. In light of the increasing incidences of these disorders in societies with aging populations, there is an urgent need to further improve treatment options.

HYPOTHESIS: Phytotherapy modulates diseases and symptoms by addressing multiple rather than single targets. Therefore, phytotherapy might be suited to treat complex diseases such as neurocognitive disorders.

METHODS AND BACKGROUND: We performed a systematic review of the literature with defined search terms using the PubMed database. The search terms were: [(network pharmacology) OR (systems pharmacology) OR (microarray) OR (proteomic) OR (metabolomic) OR (transcriptomic) OR (RNA-seq)] AND [Alzheimer) OR (dementia)]. These search strings were connected with [(herbal) OR (botanical)] for polyherbal formulations and [(phytochemical) OR (natural product)] for single-herb preparations. Systems biology focuses on the human organism as dynamic networks that cooperate in an orchestrated manner in the healthy as well as in the diseased body. The diseasome concept integrates disease phenotypes with hierarchical networks across various biological levels-organ networks, cellular networks, and signaling networks. Network pharmacology aims to interfere with such networks to treat complex, multifactorial diseases. Diseases may be caused by exposure to external factors harmful to health (exposomes). Phytotherapy might beneficially influence diseasomes thus restoring disturbed networks. Here, the "phytome" which integrates herbal drug ingredients into the exposome may be a rich source with which to counteract diseased networks.

RESULTS: Our literature search identified 642 hits. The final number of papers included was 41. Using sophisticated animal models (transgenic mice, injection of amyloid β fragments or specific chemicals, surgical interventions) conditions have been generated that resemble Alzheimer's disease, vascular dementia, and other types of dementia. Brain tissues (mainly hippocampus and cortex), blood serum, urine, and feces were investigated using metabolomic, proteomic, and transcriptomic methods. In these experimental dementia models, specific signaling networks were reported to be affected: they regulate pathophysiological mechanisms of inflammation, signal processing and transmission, neuroplasticity, vascular function and blood, cellular integrity and metabolism as well as cellular redox balance. About two dozen polyherbal formulations (mainly derived from traditional Chinese medicine) were used for treatment in these models and partially or fully restored not only the diseased networks (diseasomes) but also the disease symptoms. Another dozen mono-herbal preparations were used to treat dementia in experimental models, and similar beneficial effects were observed.

CONCLUSION: The selected 41 papers from the literature provided a good basis for a detailed analysis of the role of network pharmacology in understanding the multimodal modes of action of herbal preparations in neurocognitive disorders. Complex signaling networks add valuable new information to classical pharmacology. The understanding of phytopharmaceuticals' modes of action underpin the necessity to expand the search from classic pharmacological models to complex network interactions.},
}

@article {pmid41166828,
year = {2025},
author = {Gomes, LS and Schüler, MCGM and Giannini, GB and Zapp, E and de Oliveira, AS and Nascimento, V},
title = {Multifunctional Carvacrol-based Organoselenium hybrids as anticholinesterase and antioxidant candidates for Alzheimer's therapy.},
journal = {Bioorganic & medicinal chemistry},
volume = {132},
number = {},
pages = {118447},
doi = {10.1016/j.bmc.2025.118447},
pmid = {41166828},
issn = {1464-3391},
abstract = {BACKGROUND: Alzheimer's Disease (AD) is a progressive neurodegenerative disorder with no curative treatment available. Acetylcholinesterase (AChE) inhibition remains a validated approach for symptomatic management. Natural compounds such as carvacrol and selenium-based organochalcogenides are promising due to their antioxidant and neuroprotective properties.

OBJECTIVES: This study aimed to design, synthesize, and evaluate twelve selenium-containing carvacrol derivatives as multifunctional anti-Alzheimer agents.

METHODS: The compounds were synthesized via copper-catalyzed azide-alkyne cycloaddition (CuAAC), forming triazole-linked hybrids. Structural characterization was performed using NMR and HRMS. Biological evaluation included in vitro AChE inhibition assays (IC50 determination), antioxidant profiling by cyclic voltammetry, and cytotoxicity screening. Computational studies involved molecular docking (GOLD software), DFT calculations, and ADMET predictions using pkCSM and SwissADME platforms.

RESULTS: Compounds 18e and 18h showed the most potent AChE inhibition (IC50 = 75 and 93 nM, respectively), exhibiting strong interactions with key residues such as Trp286 and Tyr341. Electrochemical assays identified 18l, 18f, and 18c as the most antioxidant derivatives, based on their low oxidation energy. ADMET predictions indicated high intestinal absorption (>95 %), BBB permeability, and no violations of Lipinski's rules. A strong correlation (R[2] = 0.9377) between docking scores and experimental IC50 values supported the reliability of the in silico screening.

CONCLUSION: The synthesized selenium-carvacrol hybrids exhibit a favorable combination of enzyme inhibition, antioxidant capacity, and pharmacokinetic properties. Compounds 18e and 18h demonstrated the most potential and represent valuable leads for future in-depth pharmacological studies and rational optimization in the context of Alzheimer's therapy.},
}

@article {pmid41165744,
year = {2025},
author = {Xiong, S and Cui, M and Liu, H and Wu, L and Xiong, X and Zhang, S and Yang, J and Wang, P},
title = {Rational Design of a Dual-Channel Fluorescent Probe for the Simultaneous Imaging of Brain Amyloid-β Plaques and HClO/ClO[-] in Alzheimer's Disease.},
journal = {Analytical chemistry},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.analchem.5c04718},
pmid = {41165744},
issn = {1520-6882},
abstract = {Alzheimer's disease (AD) is the most prevalent form of dementia. The pathological hallmarks of AD are characterized by the presence of amyloid-β (Aβ) plaques and elevated production of hypochlorous acid (HClO/ClO[-]) in the brain. However, there is a lack of effective tools to image the biological functions of Aβ aggregates and HClO/ClO[-] in the AD brain. In this study, we presented the first single-molecule fluorescent probe, CTAD-MB, capable of detecting both Aβ aggregates and HClO/ClO[-]. The design strategy for this probe combines an N,N-dimethyl-phenylcoumarin moiety, which has high affinity for Aβ aggregates, with a methylene blue derivative that specifically responds to hypochlorite. This bifunctional fluorescent probe provided distinct fluorescent signals for Aβ aggregates and HClO/ClO[-]. CTAD-MB demonstrated completely independent spectral responses to Aβ and HClO/ClO[-], offering high selectivity, sensitivity, and rapid response. The probe was successfully employed in imaging the HClO/ClO[-] stimulated by Aβ aggregates in PC12 cells. Also, it was effectively applied for dual-channel detection of Aβ and HClO/ClO[-] in the live AD mouse, which could be used to distinguish from the brain inflammation mouse. This insight not only advances our understanding of AD but also provides new avenues for its diagnosis and treatment.},
}

@article {pmid41165739,
year = {2025},
author = {Dalal, N and Jaiswal, J and Kushwaha, M and Verma, H and Rana, P and Gupta, S and Panwar, R and Janmeda, P and Jain, P and Singh, AK and Mohan, A and Kumar, A},
title = {Implications of Gut Microbiota-Derived Metabolites in Neurological Disorders.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.5c00414},
pmid = {41165739},
issn = {1948-7193},
abstract = {Neurological disorders (NDs) represent a significant global health challenges, with neurodegeneration being a common pathological feature. Recent investigations indicate the involvement of gut microbiota-derived metabolites in these disorders, such as neuroinflammation, oxidative stress, and cognitive decline. The gut-brain axis, a communication network between the gut and the central nervous system (CNS), is influenced by microbial metabolites, which can cross the blood-brain barrier and impact brain function. Key metabolites such as trimethylamine N-oxide (TMAO), para-cresol sulfate (pCS), 4-ethylphenyl sulfate (4-EPS), and indoxyl sulfate (IS) have been linked with the progression of neurological disorders. TMAO disrupts blood-brain barrier integrity, promotes oxidative stress, and activates microglial cells, which lead to the apoptosis of neurons, resulting in neuroinflammation. This could also result in psychiatric changes and behavioral disorders. pCS produced from gut bacteria metabolizing dietary proteins is correlated with amplified oxidative stress, neuroinflammation, and cognitive impairments in disorders like Parkinson's disease and Alzheimer's disease. Similarly, elevated 4-EPS levels are linked to autism spectrum disorder, contributing to anxiety-like behavior and blood-brain barrier disruption. Understanding the mechanisms by which gut-derived metabolites affect neurological health could lead to novel therapeutic strategies that can target gut microbiota for the medication and treatment of neurological disorders. Dietary precursors and gut microbiota metabolites, modulated by probiotics, prebiotics, postbiotics, and synbiotics, play a critical role in maintaining microbiota homeostasis and influencing neurological health, needing sophisticated biosensors to enable real-time monitoring and early intervention in disorders linked to gut metabolite imbalances.},
}

@article {pmid41165158,
year = {2025},
author = {Hao, J and Wan, Q and Chen, C},
title = {Atractylenolide III Promotes Astrocyte Aβ Clearance by Up-regulating AQP4 to Improve Alzheimer's Disease.},
journal = {Folia biologica},
volume = {71},
number = {3},
pages = {140-148},
doi = {10.14712/fb2025071030140},
pmid = {41165158},
issn = {0015-5500},
support = {D202303076913//Health Commission of Hunan Province/ ; D202304017019//Health Commission of Hunan Province/ ; },
mesh = {*Astrocytes/metabolism/drug effects ; Animals ; *Aquaporin 4/metabolism/genetics ; *Amyloid beta-Peptides/metabolism ; *Sesquiterpenes/pharmacology/therapeutic use/chemistry ; *Alzheimer Disease/drug therapy/metabolism ; *Lactones/pharmacology/therapeutic use/chemistry ; Mice ; *Up-Regulation/drug effects ; Molecular Docking Simulation ; Male ; Disease Models, Animal ; Cell Survival/drug effects ; Mice, Inbred C57BL ; Peptide Fragments/metabolism ; },
abstract = {Astrocytes actively phagocytose amyloid beta (Aβ), enhancing cerebral clearance and positioning themselves as viable therapeutic targets for Alz-heimer's disease (AD). Atractylenolide III (ATL-III), the primary bioactive compound in the traditional Chinese herb Baizhu, demonstrates established neuroprotective properties. However, the research on its effects on astrocytes has not yet been elaborated. To induce an astrocyte-based AD model, Aβ1-42 was utilized. Cell viability assays were conducted to screen for the optimal concentration of ATL-III treatment. Molecular docking was performed to investigate the binding between ATL-III and aquaporin 4 (AQP4). Additionally, an Aβ1-42-induced AD mouse model was adopted. In this study, ATL-III effectively reduced the accumulation level of Aβ1-42 in the cell supernatant, and at the same time, significantly enhanced the internalization of Aβ by astrocytes. Of interest, the study reveals that ATL-III not only has the property of binding to AQP4 but also up-regulates the expression level of this protein. Mechanistic probes suggest that the role of ATL-III in promoting Aβ clearance by astrocytes may be partially dependent on its regulation of AQP4 expression. Animal behavioural experiments confirmed that the compound ameliorated Aβ1-42-induced cognitive dysfunction, and pathological analyses revealed significantly elevated AQP4 expression in the hippocampus. The combined findings suggest that ATL-III may play a role in ameliorating the pathological process of AD by enhancing the efficiency of astrocyte-mediated Aβ clearance through the up-regulation of AQP4 expression.},
}

*Astrocytes/metabolism/drug effects
Animals
*Aquaporin 4/metabolism/genetics
*Amyloid beta-Peptides/metabolism
*Sesquiterpenes/pharmacology/therapeutic use/chemistry
*Alzheimer Disease/drug therapy/metabolism
*Lactones/pharmacology/therapeutic use/chemistry
Mice
*Up-Regulation/drug effects
Molecular Docking Simulation
Male
Disease Models, Animal
Cell Survival/drug effects
Mice, Inbred C57BL
Peptide Fragments/metabolism

@article {pmid41165142,
year = {2025},
author = {Chen, YN and Xiong, ZE and Wen, X and He, SJ and Zhang, XL and Zhang, R and Wang, T and Zou, J},
title = {Anthocyanins in the treatment of Alzheimer's disease: a systematic review and meta-analysis of animal studies.},
journal = {Nutritional neuroscience},
volume = {},
number = {},
pages = {1-18},
doi = {10.1080/1028415X.2025.2578641},
pmid = {41165142},
issn = {1476-8305},
abstract = {BACKGROUND: To comprehensively evaluate the therapeutic potential of anthocyanins in animal models of Alzheimer's disease (AD).

METHODS: The PubMed, Web of Science, and Embase databases were searched for preclinical animal studies investigating anthocyanin intervention in AD models up to June 2025. Studies reporting outcomes related to cognitive behavior, neuropathological changes such as amyloid-β (Aβ) deposition, or molecular mechanisms including oxidative stress and inflammatory markers, were included in the analysis. Data analysis was performed using RevMan 5.4 software. The SYRCLE tool was used to assess the risk of bia.

RESULTS: Anthocyanin intervention significantly improved cognitive function in animal models of AD. Meta-analysis revealed that in the Morris water maze test, the anthocyanin treatment group exhibited a significantly higher number of crossings in the target quadrant compared to the control group (SMD = 1.83, 95% CI: 1.48 -2.18, p < 0.00001). Regarding pathological indicators, anthocyanin administration was associated with a significant reduction in Aβ protein deposition (SMD = -5.39, 95% CI: - 6.89 to - 3.88, p < 0.00001). Furthermore, anthocyanin effectively alleviated oxidative stress, as evidenced by a significant decrease in malondialdehyde (MDA) levels (SMD = -4.19, 95% CI: - 6.76 to - 1.63, p = 0.001). In terms of neuroinflammatory markers, anthocyanin treatment significantly reduced the expression levels of tumor necrosis factor-alpha (TNF-α) (SMD = -3.30, 95% CI: - 4.91 to - 1.68, p < 0.0001) and interleukin-1 beta (IL-1β) (SMD = -2.23, 95% CI: - 3.12 to - 1.34, p < 0.00001).

CONCLUSION: This systematic review and meta-analysis suggest that anthocyanins could improve cognitive function and mitigate neuropathology in animal models of AD.},
}

@article {pmid41164883,
year = {2025},
author = {André, C and Stankeviciute, L and Michaelian, JC and Antonsdottir, IM and Benca, RM and Coulthard, EJ and D'Rozario, AL and Dijk, DJ and Gimenez, S and Gorgoni, M and Leng, Y and Lucey, BP and Pase, MP and Rainey-Smith, SR and Rosenzweig, I and Spira, AP and Winer, JR and Rauchs, G and Naismith, SL and , },
title = {International recommendations for sleep and circadian research in aging and Alzheimer's disease: A Delphi consensus study.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {10},
pages = {e70742},
doi = {10.1002/alz.70742},
pmid = {41164883},
issn = {1552-5279},
support = {//Alzheimer's Association International Society/ ; //Advance Alzheimer's Research and Treatment/ ; //Sleep and Circadian Rhythms/ ; //PIA membership, ISTAART,/ ; /ALZ/Alzheimer's Association/United States ; },
mesh = {Humans ; *Alzheimer Disease/physiopathology ; Delphi Technique ; *Aging/physiology ; *Circadian Rhythm/physiology ; Consensus ; *Sleep/physiology ; *Sleep Wake Disorders ; *Biomedical Research ; },
abstract = {INTRODUCTION: Research in the field of sleep, aging, and dementia is rapidly growing. Consensus guidance is needed to facilitate high-quality research, comparability, and consistency.

METHODS: A modified Delphi consensus study was conducted by the Sleep and Circadian Rhythms Professional Interest Area of the International Society to Advance Alzheimer's Research and Treatment (ISTAART) and an international panel of experts to establish recommendations for future research.

RESULTS: After two voting rounds, the group (1) determined by consensus the most relevant sleep and circadian features to assess in the context of aging and dementia research, (2) established recommendations on data acquisition and report for future studies, and (3) identified high-priority future directions.

DISCUSSION: This expert consensus study provides guidance to develop high-quality sleep and circadian research in the context of aging and dementia. Similar recommendations will need to be established for clinical practice.

HIGHLIGHTS: We report the results of an international expert consensus study. Sleep and circadian rhythms features relevant to aging and dementia were identified. Recommendations on data acquisition and reporting were established. High-priority future research directions were identified.},
}

Humans
*Alzheimer Disease/physiopathology
Delphi Technique
*Aging/physiology
*Circadian Rhythm/physiology
Consensus
*Sleep/physiology
*Sleep Wake Disorders
*Biomedical Research

@article {pmid41164820,
year = {2025},
author = {Summanwar, D and Owora, AH and Ben Miled, Z and Dexter, PR and Kulshreshtha, A and Strunk, S and Jiang, B and Coppedge, K and Disla, S and Galvin, JE and Boustani, M and Fowler, NR},
title = {Prevalence of Multiple Chronic Conditions in Older Adults with Undiagnosed Mild Cognitive Impairment and Alzheimer's Disease and Related Dementias in Primary Care.},
journal = {Clinical interventions in aging},
volume = {20},
number = {},
pages = {1799-1809},
pmid = {41164820},
issn = {1178-1998},
mesh = {Humans ; Aged ; *Cognitive Dysfunction/epidemiology/diagnosis ; Male ; Female ; Cross-Sectional Studies ; *Primary Health Care/statistics & numerical data ; *Alzheimer Disease/epidemiology/diagnosis ; Aged, 80 and over ; Prevalence ; *Multiple Chronic Conditions/epidemiology ; Indiana/epidemiology ; Florida/epidemiology ; *Dementia/epidemiology/diagnosis ; },
abstract = {BACKGROUND: Most adults aged ≥65 years live with multiple chronic conditions (MCC), and nearly one in four have recognized or unrecognized Alzheimer's disease and related dementias (ADRD), including an estimated 7.2 million Americans. Together, MCC and ADRD increase treatment complexity, medication burden, and the risk of adverse outcomes. Among patients who meet clinical criteria for mild cognitive impairment (MCI) or ADRD but lack a formal diagnosis, MCC burden remains unclear. This study examined the association between MCC burden and undiagnosed MCI and ADRD in a diverse cohort of older adults in primary care.

METHODS: We conducted a cross-sectional analysis of 324 adults aged ≥65 from primary care clinics in Indiana and South Florida (2021-2023), as part of a larger ADRD detection study. Patients without documented MCI or ADRD completed standardized cognitive assessments. Cognitive status (normal, MCI, ADRD) was determined by interdisciplinary consensus. Chronic conditions and medications were extracted from electronic health records. Multinomial logistic regression was used to examine the association between MCC profiles and cognitive status.

RESULTS: Among 324 older adults, 51.9% were determined to have MCI and 8% ADRD. Patients with MCI and ADRD had more chronic conditions (mean = 5-6) and medications (mean = 4-5) than those with normal cognition (p < 0.001). Anticholinergic use was more common in the MCI (23.8%) and ADRD (23.1%) groups than in those with normal cognition (10.8%). In adjusted models, MCI and ADRD were associated with higher odds of having more chronic conditions. Cerebrovascular disease was associated with both MCI and ADRD; diabetes, sleep apnea, and insomnia with MCI; and ischemic heart disease and insomnia with ADRD.

CONCLUSION: Older adults with unrecognized MCI and ADRD experience substantial MCC and medication burden. These findings highlight the need for targeted primary care interventions that integrate cognitive screening, support MCC management, optimize self-management capacity, and promote safer prescribing.},
}

Humans
Aged
*Cognitive Dysfunction/epidemiology/diagnosis
Male
Female
Cross-Sectional Studies
*Primary Health Care/statistics & numerical data
*Alzheimer Disease/epidemiology/diagnosis
Aged, 80 and over
Prevalence
*Multiple Chronic Conditions/epidemiology
Indiana/epidemiology
Florida/epidemiology
*Dementia/epidemiology/diagnosis

@article {pmid41164318,
year = {2025},
author = {Yaghmaei, E and Dillard, A and Rezaei, M and Rezaie, A and Pierce, A and Lu, H and Adams, E and Todorov, N and Ehwerhemuepha, L and Zheng, J and Sajjadi, SA and Bazargan, M and Rakovski, C},
title = {Comprehensive descriptive analysis of large Alzheimer's disease patient cohorts.},
journal = {Journal of Alzheimer's disease reports},
volume = {9},
number = {},
pages = {25424823251385560},
pmid = {41164318},
issn = {2542-4823},
abstract = {BACKGROUND: Precise estimates of the prevalence of Alzheimer's disease (AD), the distribution of demographic characteristics, comorbidities, treatment plans, insurance types, cost of treatment and survival probabilities at various time points are crucially important to advancing our understanding and for improving future AD research studies.

OBJECTIVE: We analyzed two of the largest and high-quality medical databases, Oracle EHR Real-World Data and IQVIA. The results provide the most complete description of the AD patients in the US.

METHODS: We present high-accuracy summary statistics of many important variables related to AD patients. Proportions, means and 95% confidence intervals were provided for all levels of the categorical and quantitative variables.

RESULTS: We report high accuracy estimates of the overall survival probabilities for the first five years after initial diagnosis, drug treatments and patterns of use, demographics, insurance types, hospitalization duration, number of hospital visits, and a detailed list of comorbidities. We also report estimates of the annual total average cost of treatment per patient as well as itemized allocations for drugs, hospitalizations, surgery, and management costs.

CONCLUSIONS: We present the most complete, detailed and high-accuracy descriptive analysis of AD patients to date.},
}

@article {pmid41164084,
year = {2025},
author = {Zhu, L and Cai, M and Lu, Z and Wang, Q and Zhai, T and Hu, J},
title = {The impact of high-intensity interval training on cerebrovascular function in the APP/PS1 mice.},
journal = {Frontiers in aging},
volume = {6},
number = {},
pages = {1647628},
pmid = {41164084},
issn = {2673-6217},
abstract = {ABSTRACT: Alzheimer's disease (AD), the most commonly diagnosed form of senile dementia worldwide, is closely associated with aging and distinct neuropathological features. Recent studies highlight that up to 90% of individuals, either preclinical or clinical, diagnosed with vascular pathology in the context of AD exhibit thickening and hyalinization of the media in small and medium-sized cerebral vessels. Exercise has emerged as a potential, non-pharmaceutical, and cost-effective intervention for the prevention and treatment of AD. However, there is limited research exploring the effects of high-intensity interval training (HIIT) on cerebrovascular function in AD.

METHODS: Four-month-old female C57BL/6 J mice and APP/PS1 transgenic mice were initially acclimated to a standard diet for 1 week. The two groups were then divided into sedentary and exercise cohorts, with the exercise group engaging in a 6-week HIIT regimen. Post-intervention, hippocampal specimens were collected for analysis. Aβ and Tau protein levels were measured to assess AD pathology, while cognitive function was evaluated using the eight-arm radial maze and BDNF mRNA expression. Additionally, markers of cerebrovascular function-including VEGF, EPO, eNOS, GPR68, and ET-1-were examined, and HIF-1α was utilized to assess the hippocampal response to AD pathology.

RESULTS: HIIT significantly reduced reference memory errors (p = 0.025) and markedly upregulated Bdnf mRNA expression (p < 0.001) specifically in APP/PS1 mice. Furthermore, HIIT significantly decreased protein levels of AD pathological markers p-TAU (p = 0.001) and APP (p = 0.002) in APP/PS1 mice. HIIT significantly increased the mRNA (p < 0.001) and protein (p = 0.003) levels of EPO and Vegfa mRNA (p < 0.001) levels to stimulate pro-angiogenic signal in APP/PS1 mice. HIIT also significantly increased both the mRNA and proteins levels of eNOS expression (p < 0.001) while decreasing the mRNA and proteins levels of ET-1 (p < 0.001) and GPR68 (p < 0.001) to enhance vasodilation in APP/PS1 mice. Finally, HIIT significantly increased HIF-1α expression at both protein and mRNA levels (p < 0.001), independent of genotype.

CONCLUSION: HIIT ameliorates cognitive function and reduces hallmark AD pathology. This positive effect is potentially mediated through cerebral microangiogenesis, cerebrovascular function regulation, and hypoxic metabolism. HIIT represents a promising non-pharmacological strategy for targeting multiple aspects of AD pathophysiology.},
}

@article {pmid41163934,
year = {2025},
author = {Jafari, M and Alipour, M and Zamani, S and Mohtasham Amiri, A and Pourabbas, P and Hasannejad-Bibalan, M},
title = {Probiotics as a Complementary Medicine in Neurologic Disorders.},
journal = {Health science reports},
volume = {8},
number = {11},
pages = {e71422},
pmid = {41163934},
issn = {2398-8835},
abstract = {BACKGROUND AND AIMS: Today, neurological and neuropsychiatric disorders, including depression, anxiety, Parkinson's disease (PD), Alzheimer's disease (AS), autism spectrum disorder (ASD), and multiple sclerosis (MS), contribute significantly to global disability and healthcare burden. Most current treatment options only provide symptomatic relief and are limited by challenges such as drug resistance, systemic side effects, and poor blood-brain barrier permeability. The growing interest in the gut-brain axis has encouraged exploration of the gut microbiota as a potential therapeutic target. Probiotics-live microorganisms that may confer health benefits to the host-have been proposed to modulate the gut-brain axis through immune, metabolic, and neurochemical pathways.

METHODS: In this narrative review, a targeted search was performed across multiple databases to identify relevant articles, from which the key relationships and strategies were extracted. Then, we represented the findings to provide a comprehensive overview of the topic and highlight emerging trends and gaps in the literature.

RESULTS: Emerging preclinical and clinical studies suggest that specific probiotic strains can improve neurological symptoms by reducing neuroinflammation, supporting gut barrier integrity, and influencing neurotransmitter production. However, findings remain heterogeneous due to strain specificity, individual microbiome diversity, and methodological differences across studies. Preclinical and clinical studies suggest that specific probiotic strains can improve neurological symptoms by reducing neuroinflammation, enhancing gut barrier integrity, and influencing neurotransmitter production. Evidence supports their potential as adjunctive treatments for major neurological and neuropsychiatric disorders, including depression, anxiety, ASD, PD, AD, and MS, particularly in patients with gut dysbiosis or gastrointestinal comorbidities. However, findings remain heterogeneous due to strain specificity, individual microbiome variability, and methodological differences across studies.

CONCLUSION: This brief review summarizes the current evidence on the use of probiotics in neurological disorders, discusses potential mechanisms of action, and highlights safety considerations and limitations. Future directions include personalized probiotic therapies, large-scale randomized controlled trials, and integration with conventional neurological therapies. Overall, probiotics could be a low-risk, complementary option in the evolving field of neurotherapy, but more rigorous evidence is needed before definitive clinical recommendations can be made.},
}

@article {pmid41163844,
year = {2025},
author = {Kurban, B and Sağlık Özkan, BN and Osmaniye, D and Levent, S and Özkay, Y and Kaplancıklı, ZA},
title = {Structure-based design, synthesis, and biological activity evaluation of chalcone-piperazine derivatives as dual AChE and MAO B inhibitors.},
journal = {RSC advances},
volume = {15},
number = {48},
pages = {40897-40911},
pmid = {41163844},
issn = {2046-2069},
abstract = {The development of pharmaceutical compounds for the treatment of Alzheimer's Disease (AD) and other neurodegenerative diseases is crucial, as the pathophysiology of AD remains incompletely understood and effective treatments are still lacking. In this study, a series of novel compounds based on Donepezil, incorporating piperazine and chalcone structures, were designed, synthesized, and characterized. The structures of the compounds were confirmed using IR, [1]H-NMR, [13]C-NMR, and HRMS techniques. Biological activities of the compounds were evaluated against cholinesterase enzymes and monoamine oxidase enzymes. The most potent derivative against acetylcholinesterase (AChE) was compound 4g, with an IC50 value of 0.027 ± 0.001 μM, and the most potent against monoamine oxidase B (MAO B) was also 4g, with an IC50 value of 0.114 ± 0.003 μM. In silico studies further elucidated the interaction of compound 4g with AChE. Molecular docking revealed key interactions between 4g and amino acids in the AChE active site. A 100 ns molecular dynamics simulation confirmed the stability of the 4g-AChE complex.},
}

@article {pmid41163274,
year = {2025},
author = {Sanghvi, G and Deepak, A and R, R and Ariffin, IA and Kashyap, A and Chahar, M and Nanda, A and Ray, S and Joshi, KK},
title = {Chondroitinase ABC in Neural Regeneration: Advances in CNS and Peripheral Nerve Repair.},
journal = {Current pharmaceutical design},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113816128392818251012115510},
pmid = {41163274},
issn = {1873-4286},
abstract = {Chondroitinase ABC (ChABC) is a bacterial enzyme that can potentially address the inhibitory effects of Chondroitin Sulfate Proteoglycans (CSPGs) in various neurological disorders and injuries. CSPGs are key components of the extracellular matrix that, when accumulated after Central Nervous System (CNS) injury or neurodegenerative diseases, inhibit axonal growth and tissue repair. This review explores the therapeutic potential of ChABC in Spinal Cord Injury (SCI), Traumatic Brain Injury (TBI), stroke, Parkinson's Disease (PD), Alzheimer's Disease (AD), and peripheral nerve regeneration. ChABC's mechanism of action involves the degradation of CSPGs, promoting neural plasticity, axonal regeneration, and functional recovery in SCI and other CNS injuries. In stroke and TBI, ChABC treatment has been shown to enhance neurogenesis, reduce glial scar formation, and support neuronal survival. In neurodegenerative conditions like PD and AD, ChABC's ability to modify the inhibitory extracellular environment offers novel strategies for promoting neuronal repair and cognitive function. Additionally, ChABC has been explored in cancer therapy, where its ability to degrade the tumor extracellular matrix facilitates improved drug delivery and tumor infiltration. While ChABC holds promise, challenges remain in its clinical application, particularly regarding stability, targeted delivery, and long-term effects. This review discusses the mechanism of action of ChABC and various delivery strategies, including viral vectors and localized infusion, and emphasizes the need for further research to optimize ChABC's potential. The future of ChABC in regenerative medicine depends on overcoming these barriers, improving delivery methods, and exploring synergistic treatments for enhanced recovery outcomes.},
}

@article {pmid41163120,
year = {2025},
author = {Juan, Y and Wei, T and Weiwei, Z and Dongdong, S and Mengjie, Z and Xuefeng, W and Xianglong, L and Yuelong, S and Jinhua, Z and Xiumei, L},
title = {Regulation on microbial composition,serotonergic synapse, and apoptotic signaling pathway by extracts fromSonchus brachyotus DC. (SBE) to improve ethanol-induced acute oxidative stress in mice.},
journal = {Microbiome},
volume = {13},
number = {1},
pages = {221},
pmid = {41163120},
issn = {2049-2618},
support = {CAAS-IFR-ZDRW202406//The Agricultural Science and Technology Innovation Program/ ; },
mesh = {Animals ; *Oxidative Stress/drug effects ; Mice ; *Gastrointestinal Microbiome/drug effects ; *Apoptosis/drug effects ; Signal Transduction/drug effects ; *Plant Extracts/pharmacology ; Ethanol/toxicity/adverse effects ; Male ; *Synapses/drug effects/metabolism ; Bacteria/classification/genetics/drug effects/isolation & purification ; Antioxidants/pharmacology ; *Sonchus/chemistry ; RNA, Ribosomal, 16S/genetics ; },
abstract = {BACKGROUND: Oxidative stress has been firmly established as a pivotal contributor to the pathogenesis of inflammatory bowel disease, diabetes mellitus, Alzheimer's disease, and other multifactorial disorders. Our previous findings have demonstrated the extracts from Sonchus brachyotus DC. (SBE) mitigates intestinal oxidative stress through interactions between the oxidative stress biomarkers and gut microbiota. However, we did not focus on the mechanism by which SBE exerts antioxidant stress effects through regulating metabolites and genes, nor the correlation between the two and gut microbiota. Therefore, this study aimed to elucidate the underlying mechanism by which SBE mitigates oxidative stress through the gut microbiota, metabolites, and genes.

RESULTS: Supplementation with SBE exerts a promising regulatory effect on oxidative stress by modulating key oxidative stress biomarkers (e.g., GSH, SOD, etc.) in serum, intestine, liver, and brain tissues in ethanol-model mice. And the SBE treatment exhibited a notable reparative effect on intestine, liver, and brain tissue damage. Concomitantly, 16S rRNA and ITS sequencing revealed significant alterations in the composition of intestinal bacteria and fungi in SBE-treated mice, suggesting the restoration of gut microbiota homeostasis. Spearman correlation analysis further indicated significant associations (p < 0.05) between gut microbes, particularly fungal genera, and oxidative stress biomarkers. Notably, the abundance of specific fungal genera (Alternaria and Pichia), the levels of 14,15-DiHETrE, 5-Hydroxyindole-3-acetic acid, and prostaglandin C2 key metabolites of the serotonergic synapse pathway, and the expression of Fas and Tnfsf10 key genes of apoptosis signaling pathway were significantly correlated (p < 0.05) based on the constructed correlation network. This mechanism likely triggers coordinated changes in metabolites and gene expression associated with the serotonergic synapse and apoptosis signaling pathways, ultimately leading to multi-targeted amelioration of oxidative stress. Molecular docking further revealed that trigonelline, mesaconic acid, and salicylic acid, bioactive components of SBE, may exhibit considerable binding affinity with Fas and Tnfsf10, providing a potential structural basis for SBE's regulatory effects on oxidative stress via modulation of the apoptotic signaling.

CONCLUSIONS: The antioxidant effects of SBE likely involve multi-pathway and multi-target mechanisms, consistent with the combinatorial properties of its herbs constituents. These findings lays a foundation for subsequent research. Video Abstract.},
}

Animals
*Oxidative Stress/drug effects
Mice
*Gastrointestinal Microbiome/drug effects
*Apoptosis/drug effects
Signal Transduction/drug effects
*Plant Extracts/pharmacology
Ethanol/toxicity/adverse effects
Male
*Synapses/drug effects/metabolism
Bacteria/classification/genetics/drug effects/isolation & purification
Antioxidants/pharmacology
*Sonchus/chemistry
RNA, Ribosomal, 16S/genetics

@article {pmid41162940,
year = {2025},
author = {Arif, M and Musleh, S and Alam, T},
title = {DeepB[3]Pred: blood-brain barrier peptide predictor using stacked BiGRU model with novel features.},
journal = {BMC biology},
volume = {23},
number = {1},
pages = {325},
pmid = {41162940},
issn = {1741-7007},
mesh = {*Blood-Brain Barrier/metabolism ; *Deep Learning ; *Computational Biology/methods ; *Cell-Penetrating Peptides/chemistry ; *Peptides/chemistry ; },
abstract = {BACKGROUND: The blood-brain barrier (B[3]) acts as a membrane that is a major concern in treating central nervous system (CNS) disorders. The B[3] penetrating peptides (B[3]PPs) play a significant role in delivering therapeutic drugs to a wide range of disorder diseases such as multiple sclerosis, Parkinson's disease, and Alzheimer's disease. Therefore, the correct identification of drug agents is important for the disease treatment. Generally, the computational methods are more cost effective and faster than conventional wet-lab methods in predicting B[3]PPs. Consequently, we have developed a novel deep learning-based predictor called DeepB[3]Pred that accurately predicts the B[3]PPs and non-B[3]PPs from sequence data.

RESULTS: In the proposed method, we used three types of novel features namely Pseduo residue energy content matric (PseRECM), graphical and statistical-based feature engineering (GSFE), and composition-transition and distribution (CTD)-based features. These features capture the energy-, graphical-, and compositional-based properties of from the primary peptide sequences. The data skewness is recognized as an inevitable issue that was tackled by employing a random under sampling technique. The extracted data were fed into various deep learning, i.e., stacked bidirectional gated recurrent unit (BiGRU), Deep Forest, and machine learning models, i.e., CatBoost, Support Vector Machine.   BiGRU-based DeepB[3]Pred model attained better results than the other state-of-the-art B[3]PPs predictors. The prediction efficacy of the proposed model on fivefold cross-validation in terms of accuracy is 0.945, MCC of 0.877, and area under the curve (AUC) of 0.965. The generalization performance on the unseen data is reported as 0.869 for accuracy, 0.635 for MCC, and 0.933 for AUC.

CONCLUSION: We believe our research will accelerate the peptide-based drug discovery for neurological diseases in particular.},
}

*Blood-Brain Barrier/metabolism
*Deep Learning
*Computational Biology/methods
*Cell-Penetrating Peptides/chemistry
*Peptides/chemistry

@article {pmid41161455,
year = {2025},
author = {Ishaq, K and Arputharaj, E and Khan, MB and Dahms, HU and Delattre, C and Chao, YY and Huang, YL},
title = {Turning an adversary into an ally: Self-assembled amyloid-like fibril aerogel packed 3D-printed microfluidic sample pre-treatment device for elemental analysis.},
journal = {International journal of biological macromolecules},
volume = {},
number = {},
pages = {148590},
doi = {10.1016/j.ijbiomac.2025.148590},
pmid = {41161455},
issn = {1879-0003},
abstract = {In this study, we transformed well-known disease-causing amyloid fibrils into a functional ally. Instead of using Alzheimer's disease associated amyloid-beta fibrils we employed synthetic lysozyme derived amyloid-like fibrillar aggregates. We developed a simple and effective method for enriching and detecting various toxic elements in complex serum samples. This method employs a reusable 3D-printed microfluidic sample pre-treatment device, packed with a bio-based aerogel elemental ion extractant composed of self-assembled amyloid-like lysozyme fibrillar aggregates (AF), graphitic carbon nitride nanosheets (g-C3N4 NSs), and polyethyleneimine (PEI). The developed setup is integrated with inductively coupled plasma mass spectrometry (ICP-MS), enabling accurate elemental analysis without interference from the sample matrix. The synthesized elemental ion extractant aerogel is rich in diverse functional groups, significantly enhances the element extraction efficiency compared to conventional toxic element sorbents lacking structured amyloid-like networks. The established method yielded significant detection limits ranging from 1 to 100 μg L[-1] for Ag[+], Cr[3+] and Se IV over other elements with relative standard deviations (RSDs) between 2.1 and 4.6 %. Specifically, the approach achieved a limit of detection (LOD) of 0.2 μg L[-1] for Cr, 0.4 μg L[-1] for Se, and 1.1 μg L[-1] for Ag. High recovery rates ranging from 85 to 102 % were achieved in spiked complex serum matrices. Moreover, the proposed multifunctional 3D-printed microfluidic approach significantly enhanced the selective extraction and detection of toxic elements in complex serum samples, demonstrating robust performance over seven adsorption-desorption cycles and representing a sustainable and significant analytical advancement.},
}

@article {pmid41161293,
year = {2025},
author = {Sahoo, SS and Paidesetty, SK and Sahu, PK and Pattanaik, S and Dandela, R},
title = {Therapeutic innovation through drug repurposing: A multidimensional approach toward treating Parkinson's disease.},
journal = {Bioorganic chemistry},
volume = {166},
number = {},
pages = {109129},
doi = {10.1016/j.bioorg.2025.109129},
pmid = {41161293},
issn = {1090-2120},
abstract = {Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder after Alzheimer's disease, primarily affecting the aging population. Despite the introduction of levodopa in the 1960s and significant progress in managing PD symptoms, no treatment has yet demonstrated neuroprotective efficacy. The complexity and multifactorial nature of PD continue to present substantial therapeutic challenges, prompting researchers to explore alternative approaches such as drug repurposing. This strategy offers a time- and cost-efficient route to drug development. Recent efforts have focused on repurposing agents originally developed for metabolic and other non-neurological disorders. Ongoing research is actively investigating several repurposed drugs originally intended for different conditions, including anti-hypertensives (isradipine, dexmedetomidine), anti-asthmatics (montelukast), phosphodiesterase5 inhibitors (sildenafil), antimicrobials (rifaximin), and various CNS-active agents (aripiprazole, escitalopram, paroxetine, venlafaxine, duloxetine, caffeine). While drug repurposing holds considerable promise, comprehensive preclinical and clinical studies are essential to validate these candidates for PD-specific therapeutic applications. This review aims to provide an in-depth overview of PD, encompassing its pathological and molecular characteristics, and to critically evaluate the current landscape of drug repurposing strategies to develop effective therapies for PD.},
}

@article {pmid41160917,
year = {2025},
author = {Rößler, H and Hamzehpour, L and Grimm, O},
title = {Transdiagnostic neuroanatomical risk in schizophrenia: integrating regional vulnerability indices with anthropometric and fitness-based markers of cardiometabolic health.},
journal = {NeuroImage. Clinical},
volume = {48},
number = {},
pages = {103897},
doi = {10.1016/j.nicl.2025.103897},
pmid = {41160917},
issn = {2213-1582},
abstract = {Schizophrenia is a multisystem disorder affecting both brain and body, with patients exhibiting substantial somatic comorbidities including obesity, reduced physical fitness, and elevated cardiometabolic risk. While neuroimaging-derived Regional Vulnerability Indices (RVIs) have quantified brain structural deviations from disorder-specific patterns, their relationship to physical health in schizophrenia remains largely unexplored. In this study, we combined RVIs with detailed anthropometric and fitness assessments in 42 schizophrenia patients and 43 matched healthy controls. Participants underwent MRI-based cortical thickness analyses to derive RVIs for nine psychiatric, neurological, and metabolic disorders, alongside measurements of body composition, cardiorespiratory fitness, handgrip strength, and jump performance. Patients exhibited significantly higher RVIs for schizophrenia (Cohen's D = -1.1), bipolar disorder (Cohen's D = -0.9), Alzheimer's (Cohen's D = -0.6) and Parkinson's disease (Cohen's D = -0.7), and type 2 diabetes (Cohen's D = -0.9). These overlapping neuroanatomical vulnerabilities across psychiatric, neurodegenerative, and metabolic conditions might reflect shared underlying genetic and physiological mechanisms. Principal component analysis revealed three latent dimensions: (1) general risk factors, (2) physical fitness deficits, and (3) psychosis-spectrum vulnerability, with the latter two showing significant differences between groups. These findings highlight that metabolic impairment and reduced physical fitness in schizophrenia are not merely secondary phenomena but constitute distinct dimensions of systemic vulnerability. Overall, our results support a brain-body conceptualization of schizophrenia, suggesting that RVIs may serve as biomarkers to guide precision medicine interventions integrating neuroprotective strategies with lifestyle management. Future research should incorporate longitudinal and multimodal assessments to clarify causal relationships and optimize individualized treatment approaches.},
}

@article {pmid41160464,
year = {2025},
author = {Kim, M and Kwon, H and Sohn, S and Lee, WJ and Cho, K and Kim, GW},
title = {Alzheimer's disease diagnosis and treatment: From pathophysiological insights to therapeutic advances in the era of precision neurology (2025 review).},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251391820},
doi = {10.1177/13872877251391820},
pmid = {41160464},
issn = {1875-8908},
abstract = {Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder marked by progressive cognitive decline, functional impairment, and ultimately, loss of independence. Traditional models centered on amyloid-β and tau pathology have expanded to encompass interconnected processes such as neuroinflammation, synaptic dysfunction, and gut-brain axis disruption, underscoring the multifactorial nature of the disease. In this review, we delivered that advances in diagnosis now integrate fluid biomarkers within the A/T/N/X framework, high-resolution neuroimaging, and artificial intelligence, enabling earlier and more precise disease characterization. On the therapeutic front, the approval of anti-amyloid monoclonal antibodies marks a paradigm shift toward disease-modifying approaches, yet challenges remain regarding efficacy, safety, and accessibility. Complementary strategies, including cognitive interventions and innovative drug delivery systems, highlight the need for multidimensional care that extends beyond pharmacology to improve patient quality of life. Furthermore, emerging avenues such as stem cell therapy, multitarget drug development, and precision medicine approaches illustrate a field in transition-shifting from symptomatic management toward personalized strategies aimed at altering the course of AD.},
}

@article {pmid41160460,
year = {2025},
author = {Cury, RM and da Silva, T and Cezar-Dos-Santos, F and Fakih, YRC and Narvaez, KAR and Gouvea, MC and Espínola, C and Ferreira, CF and de Castro, WAC and Pamplona, FA and Silva, EGD and Bicca, MA and Nascimento, FP},
title = {A randomized clinical trial of low-dose cannabis extract in Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251389608},
doi = {10.1177/13872877251389608},
pmid = {41160460},
issn = {1875-8908},
abstract = {BackgroundPreclinical and clinical evidence suggest that low-dose cannabinoids could ameliorate Alzheimer's disease (AD) signs and symptoms. We designed this trial to evaluate the safety and efficacy of low-dose THC-CBD balanced cannabinoid extract in the treatment of patients with AD-associated dementia.ObjectiveThe objective of this phase 2 trial was to evaluate the safety and efficacy of a balanced THC-CBD cannabinoid extract for symptomatic patients with AD.MethodsA Phase 2, randomized, double-blind, placebo-controlled, clinical trial including patients between 60 and 80 years-old diagnosed with AD-associated dementia. For 26 weeks, participants orally received either placebo or THC-CBD extract (0.350 mg/THC and 0.245 mg/CBD), daily.ResultsAt week 26, Mini-Mental State Exam total score was significantly higher in cannabis- when compared to placebo-treated patients, which was assessed using the mixed model analysis. No significant difference was detected between placebo and cannabis groups in terms of secondary outcomes and adverse events incidence.ConclusionsTo this date, this is the longest clinical trial evaluating cannabinoids effects on AD patients. We initially demonstrate that low-dose THC-CBD potentially can be an effective and safe therapeutic option for AD-related dementia. Nonetheless, larger and longer trials are necessary to confirm this finding and establish cannabinoid administration as therapy for AD dementia.Trial RegistrationThe Brazilian Registry of Clinical Trials (ReBEC) registration #U1111-1258-2058 - REBEC (ensaiosclinicos.gov.br).},
}

@article {pmid41160443,
year = {2025},
author = {Lim, MJ and Cheung, CY and Chong, JR and Chua, J and Hilal, S and Lai, MK and Maier, AB and Schmetterer, L and Tan, BY and Venketasubramanian, N and Wong, TY and Xu, X and Yeo, BT and Zhou, JH and Chen, CL},
title = {HARMONISATION - A multimodal prospective study of vascular cognitive impairment in multi-ethnic Asians: Cohort profile, progress, current contributions, and future impact.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251389006},
doi = {10.1177/13872877251389006},
pmid = {41160443},
issn = {1875-8908},
abstract = {Vascular cognitive impairment (VCI) describes cerebrovascular disease (CeVD)-associated cognitive disorders regardless of pathogenesis, ranging from a prodrome to dementia. Heterogeneity in the etiology and severity of CeVD, and significant co-occurrence with Alzheimer's disease (AD) pathology has hampered investigations. Research into VCI is especially relevant in Asia, where cognitive impairment and dementia, often due to VCI, grows due to rapidly aging populations and high prevalence of vascular risk factors. This manuscript reviewed the rationale, unique positioning, design, methodology, and findings from the HARMONISATION study, a prospective observational study of VCI and AD in multi-ethnic Asians. HARMONISATION aimed to discover and validate novel biomarkers as effective diagnostic and prognostic tools, and translate findings into improved patient care, disease management and treatment-utilizing comprehensive multimodal clinical, neuroimaging, retinal, and blood biomarker data to address critical research gaps such as the etiology and clinical importance of mixed dementia, relationships between AD and CeVD pathology, and challenges of heterogenous CeVD pathology. HARMONIZATION recruited and deeply phenotyped 700 older multi-ethnic Asians with no cognitive impairment, mild cognitive impairment, and dementia for up to 5 years of follow-up. It has yielded developments in biomarker identification, validation, interactions and analysis methods; disease mechanisms and progression; clinical prognostics for VCI and AD; improved patient care and management; and enabled future development of novel interventions in Asians, and globally. An ongoing extension study will allow up to 10 years follow-up to further explore specific modifiable processes of VCI and the contributions of vascular events to cognitive impairment.},
}