@article {pmid41350292,
year = {2025},
author = {Bolland, E and De Burca, A and Wang, SH and Khalil, A and McLoughlin, G},
title = {Efficacy of auditory gamma stimulation for cognitive decline: a systematic review of individual and group differences across cognitively impaired and healthy populations.},
journal = {npj aging},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41514-025-00305-1},
pmid = {41350292},
issn = {2731-6068},
support = {NIHR304904//National Institute for Health Research/ ; MR/N013182/1/MRC_/Medical Research Council/United Kingdom ; },
abstract = {Auditory gamma stimulation is a promising non-invasive neuromodulation technique for cognitive decline, with preclinical studies demonstrating therapeutic effects in Alzheimer's disease models. However, translating these findings into human trials has produced variable outcomes, suggesting a need to examine factors influencing efficacy. In a systematic review of 62 studies on healthy and cognitively impaired populations, we identified 16 characteristics that may affect the response to stimulation. Outcomes reported included improved cognition, slower progression of brain atrophy, and changes in functional connectivity. Optimal stimulation frequency varied across individuals, indicating that personalised approaches may be valuable. Importantly, animal-model findings regarding amyloid clearance and reduced neuroinflammation were not consistently replicated in human studies, nor did neurophysiological responses reliably predict cognitive or biological effects. Significant methodological diversity was evident, with 32 neurophysiological measures employed, highlighting a need for standardisation. Future research should prioritise consensus on outcome measurement and explore individualised intervention strategies to better assess therapeutic potential.},
}

@article {pmid41350255,
year = {2025},
author = {Oppenheimer, H and van der Meer, D and Schindler, LS and Crestol, A and Shadrin, A and Andreassen, OA and Westlye, LT and de Lange, AG and Barth, C},
title = {No causal links between estradiol and female's brain and mental health using Mendelian randomization.},
journal = {Nature communications},
volume = {16},
number = {1},
pages = {10915},
pmid = {41350255},
issn = {2041-1723},
support = {324252//Norges Forskningsråd (Research Council of Norway)/ ; 324252//Norges Forskningsråd (Research Council of Norway)/ ; 249795//Norges Forskningsråd (Research Council of Norway)/ ; 273345//Norges Forskningsråd (Research Council of Norway)/ ; 298646//Norges Forskningsråd (Research Council of Norway)/ ; 300768//Norges Forskningsråd (Research Council of Norway)/ ; 2018076//Ministry of Health and Care Services | Helse Sør-Øst RHF (Southern and Eastern Norway Regional Health Authority)/ ; 2019101//Ministry of Health and Care Services | Helse Sør-Øst RHF (Southern and Eastern Norway Regional Health Authority)/ ; 2023037//Ministry of Health and Care Services | Helse Sør-Øst RHF (Southern and Eastern Norway Regional Health Authority)/ ; 2022103//Ministry of Health and Care Services | Helse Sør-Øst RHF (Southern and Eastern Norway Regional Health Authority)/ ; 802998//EC | EU Framework Programme for Research and Innovation H2020 | H2020 Priority Excellent Science | H2020 European Research Council (H2020 Excellent Science - European Research Council)/ ; PZ00P3_193658//Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (Swiss National Science Foundation)/ ; },
mesh = {Humans ; *Estradiol/metabolism/blood ; Female ; Mendelian Randomization Analysis ; *Brain/metabolism/physiology ; Genome-Wide Association Study ; Male ; Middle Aged ; *Mental Health ; Alzheimer Disease/genetics/metabolism ; Depression/genetics/metabolism ; Adult ; Aged ; Polymorphism, Single Nucleotide ; },
abstract = {The role of estradiol in depression and Alzheimer's disease - brain disorders that disproportionately affect females - is debated. Results from observational studies are inconsistent and limited by confounding and reverse causation. To overcome these limitations, we perform two-sample Mendelian randomization. We run genome-wide association studies on sex-specific brain age gap, a proxy of brain health, and female-specific estradiol levels using data from the UK Biobank. We test for causal links between genetically-predicted factors related to estradiol exposure (estradiol levels in pre- and postmenopausal samples, reproductive span, age at menarche, age at menopause, number of childbirths) and brain age gap, Alzheimer's disease and depression as outcomes. We replicate our analyses on estradiol levels in males. Here, we find no significant associations between estradiol exposure and brain health across samples and robust methods, indicating an absence of constant causal effects and suggesting that hormonal fluctuations may drive links between estradiol and brain health.},
}

Humans
*Estradiol/metabolism/blood
Female
Mendelian Randomization Analysis
*Brain/metabolism/physiology
Genome-Wide Association Study
Male
Middle Aged
*Mental Health
Alzheimer Disease/genetics/metabolism
Depression/genetics/metabolism
Adult
Aged
Polymorphism, Single Nucleotide

@article {pmid41350163,
year = {2025},
author = {Tampi, RR},
title = {Dronabinol for Agitation in Alzheimer's Disease.},
journal = {The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jagp.2025.11.006},
pmid = {41350163},
issn = {1545-7214},
}

@article {pmid41350162,
year = {2025},
author = {Rosenberg, PB and Amjad, H and Burhanullah, H and Nowrangi, M and Vandrey, R and Pierre, MJ and Outen, JD and Schultz, M and Marano, C and Agronin, M and Wilkins, JM and Harper, D and Laffaye, T and Reardon, E and Turner, K and Ozonsi, R and Drury, M and Nguyen, A and Hasoğlu, T and Cromwell, J and Leoutsakos, JM and Forester, BP},
title = {A Randomized Controlled Trial of the Safety and Efficacy of Dronabinol for Agitation in Alzheimer's Disease.},
journal = {The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jagp.2025.10.011},
pmid = {41350162},
issn = {1545-7214},
abstract = {IMPORTANCE: Agitation in Alzheimer's disease (AD) is a great source of distress for patients and caregivers and a major public health burden. Current treatments are only modestly effective and many have safety issues including mortality risk. Novel therapeutic options are needed. There is preliminary evidence for the safety and efficacy of dronabinol (tetrahydrocannabinol, THC) for agitation in AD.

OBJECTIVE: Assess the safety and efficacy of dronabinol (THC) to decrease agitation in AD.

DESIGN: THC-AD was a 3-week randomized parallel double-blind placebo-controlled clinical trial, conducted between 2017 and 2024.

SETTING: 5 inpatient and outpatient academic clinical research centers in the Eastern U.S.

PARTICIPANTS: Volunteer sample of 75 participants meeting inclusion criteria for agitation of AD (International Psychogeriatric Association Provision Criteria) with Neuropsychiatric Inventory Clinician Version Agitation or Aggression (NPI-C A/A) domains total score of 4 or greater. Major exclusion criteria included seizure disorder, delirium, and non-AD dementia.

INTERVENTIONS: 3 weeks dronabinol vs. placebo titrated up to target dose of 10 mg daily in divided twice-daily.

MAIN OUTCOMES AND MEASURES: Prespecified co-primary agitation outcomes were the Pittsburgh Agitation Scale (PAS) and NPI-C A/A total score.

RESULTS: The majority of participants were female and were taking concomitant psychotropic medications (antidepressants and antipsychotics) at baseline. Study participants were moderately agitated at baseline, were diverse in ethnic background (9% Black, 11% Hispanic/Latina/Latino), and had severe cognitive impairment evidenced by MMSE or SIB-8. 84% completed the 3-week trial. Dronabinol decreased agitation on both primary outcomes greater than placebo to a clinically relevant extent. The fitted between-arm difference in PAS decline/week was -0.74 (SE 0.3, p = 0.015, effect size = 0.53) and for NPI-C A/A the decline was not significant at -1.26 (SE 0.67, p = 0.094, effect size = 0.36). No secondary outcomes differed between treatment arms including sleep, activities of daily living, Cohen-Mansfield Agitation Inventory (CMAI), cognition, intoxication, or use of 'as-needed' lorazepam or trazodone. Dronabinol treatment was not associated with greater intoxication nor with other adverse events (AEs) except for somnolence.

CONCLUSIONS AND RELEVANCE: Adjunctive dronabinol treatment was safe and effective for treating agitation in AD.

CLINICAL TRIALS REGISTRATION: NCT02792257.},
}

@article {pmid41350115,
year = {2025},
author = {Marien, J and Puyo-Fourtine, J and Prévost, C and Sacquin-Mora, S and Duboué-Dijon, E},
title = {Sticky Salts: Overbinding of Monovalent Cations to Phosphorylations in All-Atom Force Fields.},
journal = {Journal of chemical information and modeling},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.jcim.5c02154},
pmid = {41350115},
issn = {1549-960X},
abstract = {Phosphorylation is a major post-translational modification that is involved in the regulation of the dynamics and function of intrinsically disordered proteins (IDPs). We recently characterized a phenomenon, which we termed n-phosphate collaborations (nP-collabs), where bulk cations form stable bridges between several phosphoresidues in all-atom molecular dynamic simulations. nP-collabs were found to be sensitive to the combination of force fields and cation types. Here, we attempt to assess the physical relevance of these nP-collabs by evaluating the strength of the cation/phosphate interaction through osmotic coefficient (ϕ) calculations on the model 2Na[+]HPO4[2-] and 2K[+]HPO4[2-] salts, using different classical force fields for phosphorylations. All force fields were found to overestimate the strength of the interaction to various degrees. We thus designed new parameters for CHARMM36m and AmberFF99SB-ILDN using the Electronic Continuum Correction (ECC) approach, which provide remarkable agreement for ϕ values for both cation types and over a range of concentrations. We provide a preliminary test of these ECC parameters for phosphorylations by simulating the 7-fold-phosphorylated rhodopsin peptide 7PP and comparing secondary chemical shifts to experimental data. Conformational ensembles resulting from the ECC-derived phosphorylated force fields display both qualitative and quantitative improvements with regard to full-charge force fields. We thus conclude that long-lasting nP-collabs are artifacts for classical force fields born from the lack of explicit polarization, and propose a possible computational strategy for the extensive parametrization of phosphorylations. The presence of long-lived nP-collabs in simulations produced using classical force fields is therefore a serious concern for the accurate modeling of multiphosphorylated peptides and IDPs, which are at the center of research questions regarding neurodegenerative diseases such as Alzheimer's or Parkinson's.},
}

@article {pmid41350075,
year = {2026},
author = {Wu, G and Chen, Y and Yao, Y and Huang, W and Wu, K},
title = {Integrating network toxicology and molecular docking to uncover mechanisms of novel herbicide-induced neurodegeneration.},
journal = {Pesticide biochemistry and physiology},
volume = {216},
number = {Pt 2},
pages = {106821},
doi = {10.1016/j.pestbp.2025.106821},
pmid = {41350075},
issn = {1095-9939},
mesh = {*Herbicides/toxicity/chemistry ; *Molecular Docking Simulation ; Humans ; *Neurodegenerative Diseases/chemically induced/metabolism ; Protein Interaction Maps ; },
abstract = {Rising global reliance on novel herbicides has outpaced understanding of their potential neurotoxicity. This study employs an integrative network-toxicology pipeline to clarify how five widely used compounds, including mesotrione, topramezone, flufenazopyr, glufosinate-ammonium and beflubutamid-M, may contribute to Alzheimer's, Parkinson's, Huntington's, and amyotrophic lateral sclerosis pathogenesis. We first predicted toxic liabilities in eMolTox, SwissADME and ProTox, then harvested 310 human targets via PubChem, ChEMBL, STITCH and Swiss Target Prediction. Intersection with 3668-3429 disease genes (GeneCards/ OMIM) revealed 91-176 shared targets per disorder. PPI networks constructed in STRING and refined with Cytoscape (MCODE, cytoHubba) and novel NodeIdentifyR algorithm converged on eleven high-impact hub genes: EGFR, GSK3B, SRC, AKT1, MAPT, CASP3, MMP9, MTOR, PTK2, BCL2L1 and MAPK8. GO and KEGG enrichment analyses highlighted apoptosis, PI3K-Akt and MAPK signaling dysregulation. Single-cell and bulk transcriptomic atlases confirmed aberrant expression of these hubs in patient brains; Molecular docking demonstrated low-nanomolar affinities of all herbicides for multiple hub proteins, with mesotrione and topramezone displaying the broadest binding spectra and SRC emerging as a common high-affinity site. Molecular dynamics simulations supported stable binding in a representative herbicide-protein complex. Additionally, in vivo and in vitro experiments using Glufosinate-ammonium exposure corroborated the computational findings, underscoring the robustness of our approach. Together, these results establish a systems-level framework linking environmental herbicide exposure to neurodegeneration and nominate tractable targets for surveillance and therapeutic intervention.},
}

*Herbicides/toxicity/chemistry
*Molecular Docking Simulation
Humans
*Neurodegenerative Diseases/chemically induced/metabolism
Protein Interaction Maps

@article {pmid41349953,
year = {2025},
author = {Trubshaw, M and Kohl, O and Gohil, C and van Es, MWJ and Quinn, AJ and Yoganathan, K and Edmond, E and Proudfoot, M and Zokaei, N and Raymont, V and Pitt, J and Thayanandan, T and Thompson, AG and Talbot, K and Hu, MT and Perquin, MN and Kocagoncu, E and Rowe, JB and Woolrich, MW and Nobre, AC and Turner, MR},
title = {Divergence of cortical neurophysiology across different neurodegenerative disorders compared to healthy ageing.},
journal = {Progress in neurobiology},
volume = {},
number = {},
pages = {102865},
doi = {10.1016/j.pneurobio.2025.102865},
pmid = {41349953},
issn = {1873-5118},
abstract = {Neurodegenerative diseases involve disruption of healthy brain network communication occurring before the emergence of symptoms. Magnetoencephalography (MEG) is sensitive to the magnetic fields generated by cortical neuronal activity, and the most spatio-temporally accurate method of directly assessing neuronal activity non-invasively. We used MEG to directly compare three neurodegenerative disorders against a large healthy cohort to characterise patterns of activity deviating from healthy ageing. Task-free MEG recordings were acquired from patients with Alzheimer's disease (AD, n=29), Parkinson's disease (PD, n=25), amyotrophic lateral sclerosis (ALS, n=33) and healthy controls (HC, n=191). Healthy ageing trajectories for metrics including spectral power (local neuronal recruitment), connectivity (long-range communication), 1/f exponent (which may reflect inhibition), and oscillatory speed were extracted. These metrics were compared pairwise between HC and patient groups, correcting for age and sex. The modelled trajectories of healthy ageing included increasing beta power and oscillatory speed, with reduced power spectrum slope. PD, AD, and ALS groups all showed reductions in beta power and slowing of oscillatory activity compared to matched HC. In AD, older patients showed lower beta power compared to younger patients. Compared to matched HC, the power spectrum slope was uniquely reduced in ALS, in contrast to the increase seen in PD and AD. Gamma connectivity increased in AD and ALS. MEG has unique potential as a source of biomarkers that might be used to detect deviation from healthy ageing if applied at an earlier presymptomatic stage of neurodegeneration than current tools permit. It might also provide outcome measures for prevention trials.},
}

@article {pmid41349917,
year = {2025},
author = {Azer, L and Vanderlip, CR and Mayer, LL and Ehlert, L and Sultzer, D and Shin, HW and Stark, CEL},
title = {MST in the Wild: Optimizing the Mnemonic Similarity Task for Use in Diverse Environments.},
journal = {Neuropsychologia},
volume = {},
number = {},
pages = {109341},
doi = {10.1016/j.neuropsychologia.2025.109341},
pmid = {41349917},
issn = {1873-3514},
abstract = {BACKGROUND: Clear guidelines and tools for reliable measures of cognitive decline have yet to be established. This may be due to the absence of access to fully automated, self-administered, and scored cognitive screening tools.

METHODS: We used the optimized Mnemonic Similarity Task (oMST; Stark et al., 2023), a web computer-based self-administered tool adapted from the MST. The oMST is designed for cognitive screening and population enrichment, offering a superior alternative to traditional neuropsychological tests. We tested the oMST's reliability, validity, and accessibility across five experiments with 1,685 participants.

RESULTS: Lure discrimination was highly correlated between in-person and remote administration. These results were consistent across various testing sites, demonstrating the oMST's robustness. Importantly, visual acuity did not impact performance.

CONCLUSIONS: Our findings establish the oMST as a reliable and accessible tool for cognitive screening across diverse testing environments and administration methods, addressing critical gaps in early screening for cognitive decline.},
}

@article {pmid41349894,
year = {2025},
author = {Tang, H and Chen, X and Huang, J and Yang, Q and Liang, K and Qiu, X and Tang, J and Tian, C and Luo, N and Lin, M and Zhang, X and Wu, S and Deng, X and Lin, H and Hong, J and Wen, J and Jiang, L and Chen, P and Lin, W and Chen, W and Zhang, Y and Tan, X and Chen, Y},
title = {Characterizing patterns in causes, risk factors, and life expectancy among the oldest old (aged 95+ years).},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {102985},
doi = {10.1016/j.arr.2025.102985},
pmid = {41349894},
issn = {1872-9649},
abstract = {BACKGROUND: The global population is aging rapidly, extending into the oldest old. However, increased longevity does not always translate into enhanced health. While genetic and environmental factors influence lifespan, evidence indicates that targeted interventions can substantially enhance the likelihood of reaching 100 years. This study aimed to characterize disease and risk factor patterns among the oldest-old to identify actionable targets for promoting health and functional capacity in this rapidly growing population.

METHODS: This study identified 18 countries with the largest populations aged 95 years and older using data from the Global Burden of Disease (GBD) 2023 study and the United Nations World Population Prospects 2024. Disability-adjusted life years (DALYs), years of life lost (YLLs), and years lived with disability (YLDs) from 1990 to 2023 were quantified, ranked, and visualized across three major cause categories (non-communicable, communicable and nutritional diseases, and injuries) and risk factors (behavioral, environmental/occupational, and metabolic) by using the GBD 2023 estimates. Temporal trends were assessed using estimated annual percentage change derived from log-linear regression models, calculated separately for periods before and after the COVID-19 pandemic peak. K-means clustering was employed to identify cross-country burden patterns, with the optimal number of clusters determined via the silhouette method. Temporal trends in health-adjusted life expectancy (HALE) were examined, and frontier analysis was applied to estimate the potential for further HALE improvement across countries.

RESULTS: From 1990 to 2023, the absolute disease burden among individuals aged 95+ years increased more than fivefold, primarily driven by non-communicable diseases, accounting for ~86% of the total DALYs. Ischemic heart disease remained the leading cause, particularly for YLLs, followed by Alzheimer's disease and other dementias, which predominated in YLDs, followed by stroke and chronic kidney disease. During the COVID-19 pandemic peak (2019-2021), mental health disorders, including depression and anxiety, demonstrated a marked increase. Cluster analysis in 2023 revealed two distinct national patterns: one dominated by acute cardiovascular conditions and the other by chronic multi-system diseases. Absolute burdens of metabolic, behavioral, and environmental/occupational risk factors increased over time, although their relative contributions declined; high systolic blood pressure (YLLs), high fasting plasma glucose (YLDs), and kidney dysfunction remained the leading risk factors. The average HALE increased from 1.86 years in 1990 to 2.16 years in 2019, declined during the pandemic, and partially recovered by 2023. Frontier analysis indicated nearly a twofold potential for further HALE improvement under current socioeconomic conditions.

CONCLUSION: The 95+-year-old population exhibits distinctive patterns of disease burden that have shifted substantially over the past three decades. Despite cross-national differences, cardiometabolic diseases and risk factors, along with multisystem comorbidities from the brain and kidneys, remain the primary drivers. Integrated strategies addressing biological, social, and environmental factors may enhance intrinsic capacity and promote healthy aging in the oldest old.},
}

@article {pmid41349880,
year = {2025},
author = {Jeanne, X and Oberoi, J and Roe, MS and Baud, M and Spencer, J and Torok, Z and Vigh, L and Prodromou, C},
title = {The dihydropyridine LA1011 modulates multiple Hsp90 [_] co-chaperone interactions relevant to Alzheimer's disease.},
journal = {Cell stress & chaperones},
volume = {},
number = {},
pages = {100131},
doi = {10.1016/j.cstres.2025.100131},
pmid = {41349880},
issn = {1466-1268},
abstract = {LA1011 (dimethyl 4-(4-Trifluoro-methyl-phenyl)-2,6-bis(2-dimethylamino-ethyl)-1-methyl-1-4 dihydropyridine-3-5-dicarboxylate dihydrochloride) has been shown to improve the prognosis of Alzheimer's disease (AD) in an APPxPS1 mouse model. The target for LA1011 is the C-terminal domain of Hsp90, where it was shown previously to reduce the interaction between FKBP51 and Hsp90. FKBP51 is a Hsp90 co-chaperone that promotes the trans to cis isomerization of proline at multiple tau pSer/pThr-pro sites, thus preventing their dephosphorylation. Potentially this leads to the hyperphosphorylation of tau and the formation of neurofibrillary tangles that eventually lead to the development of AD. In this study, we demonstrate that LA1011 affects the FKBP51-mediated regulation of Hsp90, but also potentially modulates the regulation Hsp90 by the co-chaperones FKBP52, CHIP, Aha1, Hch1, and PP5. We also show that the co-chaperones HOP, CDC37 and Sgt1 appear to enhance mildly the binding of LA1011. In contrast, nucleotide alone or nucleotide with Aha1 or p23, which promote the closed conformation of Hsp90, reduce the affinity for LA1011. We conclude that LA1011 can modulate the regulatory landscape of the Hsp90 co-chaperone network, which in turn appears to improve the prognosis of Alzheimer's disease.},
}

@article {pmid41349546,
year = {2025},
author = {Lorenz, SM and Wahida, A and Bostock, MJ and Seibt, T and Santos Dias Mourão, A and Levkina, A and Trümbach, D and Soudy, M and Emler, D and Rothammer, N and Woo, MS and Sonner, JK and Novikova, M and Henkelmann, B and Aldrovandi, M and Kaemena, DF and Mishima, E and Vermonden, P and Zong, Z and Cheng, D and Nakamura, T and Ito, J and Doll, S and Proneth, B and Bürkle, E and Rizzollo, F and Escamilla Ayala, A and Napolitano, V and Kolonko-Adamska, M and Gaussmann, S and Merl-Pham, J and Hauck, S and Pertek, A and Orschmann, T and van San, E and Vanden Berghe, T and Hass, D and Maida, A and Frenz, JM and Pedrera, L and Dolga, A and Kraiger, M and Hrabé de Angelis, M and Fuchs, H and Ebert, G and Lenberg, J and Friedman, J and Scale, C and Agostinis, P and Zimprich, A and Vogt-Weisenhorn, D and Garrett, L and Hölter, SM and Wurst, W and Glaab, E and Lewerenz, J and Popper, B and Sieben, C and Steinacker, P and Zischka, H and Garcia-Saez, AJ and Tietze, A and Ramesh, SK and Ayton, S and Vincendeau, M and Friese, MA and Wigby, K and Sattler, M and Mann, M and Ingold, I and Jayavelu, AK and Popowicz, GM and Conrad, M},
title = {A fin-loop-like structure in GPX4 underlies neuroprotection from ferroptosis.},
journal = {Cell},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.cell.2025.11.014},
pmid = {41349546},
issn = {1097-4172},
abstract = {Ferroptosis, driven by uncontrolled peroxidation of membrane phospholipids, is distinct from other cell death modalities because it lacks an initiating signal and is surveilled by endogenous antioxidant defenses. Glutathione peroxidase 4 (GPX4) is the guardian of ferroptosis, although its membrane-protective function remains poorly understood. Here, structural and functional analyses of a missense mutation in GPX4 (p.R152H), which causes early-onset neurodegeneration, revealed that this variant disrupts membrane anchoring without considerably impairing its catalytic activity. Spatiotemporal Gpx4 deletion or neuron-specific GPX4[R152H] expression in mice induced degeneration of cortical and cerebellar neurons, accompanied by progressive neuroinflammation. Patient induced pluripotent stem cell (iPSC)-derived cortical neurons and forebrain organoids displayed increased ferroptotic vulnerability, mirroring key pathological features, and were sensitive to ferroptosis inhibition. Neuroproteomics revealed Alzheimer's-like signatures in affected brains. These findings highlight the necessity of proper GPX4 membrane anchoring, establish ferroptosis as a key driver of neurodegeneration, and provide the rationale for targeting ferroptosis as a therapeutic strategy in neurodegenerative disease.},
}

@article {pmid41349452,
year = {2025},
author = {Rossiter, K},
title = {Despite all our rage: An autoethnographic analysis on the role of shared affect in dementia caregiving relationships.},
journal = {Social science & medicine (1982)},
volume = {389},
number = {},
pages = {118802},
doi = {10.1016/j.socscimed.2025.118802},
pmid = {41349452},
issn = {1873-5347},
abstract = {Using an autoethnographic approach, this paper explores the phenomenon of shared rage between Alzheimer's patients and their informal family caregivers. Unlike previous analyses regarding dementia care, this work understands that rage within caregiving relationships is both dynamic and productive. Drawing broadly from social scientific studies regarding emotional labour and "feeling work," this work argues that Alzheimer's sufferers and their informal caregivers form two halves of a dyad, each of whom may use rage as a form of protection against loss of relational identity and pursuant grief, and to demand humane and dignified treatment from broken formal care systems. This individual rage simultaneously offers a point of connection between both halves of the caregiving dyad, which is otherwise torn asunder by interpersonal manifestations of the disease. Ultimately this paper argues for a brave, curious and compassionate response to caregiving dyads in which experiences of rage are not stigmatized, minimized or medicalized. Rather, this analysis suggests that experiences of anger are recognized as an often-excruciating form of emotional labour necessitated by an insidious disease and inadequate formal care systems.},
}

@article {pmid41349274,
year = {2025},
author = {Dewey, CW and Brunke, MW},
title = {Dysmetabolism of the nerve growth factor pathway in the aging brain plays a pivotal role in cognitive decline.},
journal = {Journal of the American Veterinary Medical Association},
volume = {},
number = {},
pages = {1-5},
doi = {10.2460/javma.25.09.0578},
pmid = {41349274},
issn = {1943-569X},
abstract = {Nerve growth factor (NGF) is one of several neurotrophic proteins necessary for normal development and function of the mammalian nervous system. Nerve growth factor is necessary for normal brain cholinergic function, and reduced brain cholinergic activity is a hallmark pathological feature of human Alzheimer's disease (AD). In both aging humans and transgenic rodent models, disruption of the normal NGF metabolic pathway (NGF dysmetabolism) leads to brain neuronal damage, loss of synaptic plasticity, and cognitive decline. Nerve growth factor dysmetabolism in AD patients is a gradual process, beginning years prior to the development of mild cognitive impairment. In addition to changes in the levels of specific molecular regulators of the NGF pathway, there are changes in the proportions of the 2 major receptors for NGF and its precursor (proNGF) in the brain: the tropomyosin kinase A (TrkA) receptor and the p75 neurotrophin (p75NTR) receptor. Nerve growth factor has high affinity for TrkA receptors, the stimulation of which has neuroprotective effects. The precursor of NGF has higher affinity than NGF for p75NTR receptors; stimulation of p75NTR receptors by proNGF has deleterious effects on neurons. With NGF dysmetabolism, the respective ratios of available NGF/proNGF and TrkA/p75NTR receptors are decreased, favoring neuronal damage. In rodent models genetically engineered to produce monoclonal antibodies against NGF, neuronal damage and cognitive decline occur, even when the antibodies are targeted specifically against peripheral (ie, not CNS) NGF. Because canine cognitive dysfunction is a naturally occurring model of human AD, NGF dysmetabolism may be relevant to aging dogs. This article will review details of NGF dysmetabolism and how this aberrant pathway contributes to cognitive decline.},
}

@article {pmid41349262,
year = {2025},
author = {Qi, L and Lin, L and Zheng, J and Liu, X and Liu, X and Chen, Z and Liu, L},
title = {Liraglutide improves cognitive function by reducing amyloid-beta peptide accumulation and inhibiting inflammation in 5 × FAD mice.},
journal = {The journals of gerontology. Series A, Biological sciences and medical sciences},
volume = {},
number = {},
pages = {},
doi = {10.1093/gerona/glaf265},
pmid = {41349262},
issn = {1758-535X},
abstract = {Alzheimer's disease (AD) is a degenerative disease of the central nervous system characterized by progressive memory decline. The increasing prevalence of AD has attracted considerable attention globally. The glucagon-like peptide-1 analog, liraglutide, a drug widely used in the treatment of type 2 diabetes, has shown promising neuroprotective effects in AD, including enhancing neuronal survival, reducing amyloid beta protein accumulation, improving synaptic plasticity, and reducing tau protein hyperphosphorylation. However, its potential impact on cognitive function remains unclear. We evaluated the effects of liraglutide (25 nmol/day for 8 weeks) on the cognitive ability of 12-month-old 5 × familial Alzheimer's disease (FAD) mice. The Morris water maze test was used to evaluate the spatial learning ability of mice. Histological evaluations were performed by Nissl staining and transmission electron microscopy. Neuroinflammation was detected by double immunofluorescence staining and enzyme-linked immunosorbent assay. Protein expression in the cortex and hippocampal was detected by immunohistochemistry and Western blotting. The spatial cognitive ability improved in 5 × FAD mice after liraglutide administration and was associated with an increased number of pyramidal cells in the cortex and hippocampus. Liraglutide also alleviated ultrastructural changes in the chemical synapses and reduced both local and systemic inflammation in AD mice. Furthermore, liraglutide reduced amyloid β protein expression, which may be associated with the regulation of nuclear factor kappa B/beta-secretase 1 pathways in AD mice. The potential of liraglutide to improve the cognitive function in AD mice offers an effective pharmacological approach for treating neurodegenerative diseases.},
}

@article {pmid41349232,
year = {2025},
author = {Khodadadi, S and Rezaeimanesh, N and Noormohammadi, M and Razeghi Jahromi, S and Sahraian, MA and Naser Moghadasi, A},
title = {Adherence to the MIND diet and onset of neuromyelitis optica spectrum disorder: A case-control study.},
journal = {Multiple sclerosis and related disorders},
volume = {105},
number = {},
pages = {106868},
doi = {10.1016/j.msard.2025.106868},
pmid = {41349232},
issn = {2211-0356},
abstract = {INTRODUCTION: The MIND diet (Mediterranean-DASH Intervention for Neurodegenerative Delay), which combines the Mediterranean and DASH (Dietary Approaches to Stop Hypertension) diets, improves brain function and may help postpone the onset of neurological diseases such as multiple sclerosis (MS), Alzheimer's disease (AD), and Parkinson's disease (PD). This study aimed to evaluate the association between the MIND diet and the onset of neuromyelitis optica spectrum disorders (NMOSD), a rare autoimmune disease affecting the central nervous system.

METHODS: This hospital-based case-control study included 68 patients with NMOSD and 136 controls. Data on anthropometry, dietary intake, and demographics for the year prior to enrollment were gathered using a validated 168-item semi-quantitative Food Frequency Questionnaire (FFQ). The MIND diet score was calculated based on data collected by a certified nutritionist. A logistic regression model was used to investigate the association between MIND diet adherence and the onset of NMOSD. The effect sizes are presented as adjusted odds ratios (AORs) with 95% confidence intervals (CIs).

RESULTS: Higher adherence to the MIND diet was significantly associated with a lower risk of NMOSD. Compared with the lowest tertile (T1), participants in T2 (AOR = 0.18; 95% CI: 0.03-0.89) and T3 (AOR = 0.23; 95% CI: 0.06-0.82) had lower odds of NMOSD. Consumption of green leafy vegetables (AOR = 0.14, 95% CI = 0.03-0.62), beans (AOR = 0.20, 95% CI = 0.05-0.87), whole grains (AOR = 0.06, 95% CI = 0.01-0.32), olive oil (AOR = 0.05, 95% CI = 0.01-0.24), and poultry (AOR <0.01, 95% CI = 0.00-0.01) was inversely associated with a lower risk of NMOSD across the third tertiles. Furthermore, berries (AOR = 0.40, 95% CI = 0.19-0.84) and other vegetables (AOR = 0.42, 95% CI = 0.20-0.87) showed a significant inverse association in T2 as compared to T1.

CONCLUSION: The MIND diet and some of its brain-healthy food group components, including green leafy vegetables, other vegetables, whole grains, beans, olive oil, berries, and poultry, seem to decrease the odds of NMOSD.},
}

@article {pmid41348999,
year = {2026},
author = {Jung, YH and Cho, J and Lee, SY and Seo, HE and Tak, K and Kim, WR and Park, S and Park, KH and Noh, Y},
title = {Impact of Cerebral Microbleeds on Tau-Associated Cognitive and Structural Decline.},
journal = {Neurology},
volume = {106},
number = {1},
pages = {e214453},
doi = {10.1212/WNL.0000000000214453},
pmid = {41348999},
issn = {1526-632X},
mesh = {Humans ; Female ; Aged ; Male ; *Cerebral Hemorrhage/diagnostic imaging/complications/metabolism/pathology/psychology ; *Cognitive Dysfunction/diagnostic imaging/metabolism/pathology/psychology ; *tau Proteins/metabolism ; Magnetic Resonance Imaging ; Longitudinal Studies ; Positron-Emission Tomography ; Disease Progression ; Prospective Studies ; *Alzheimer Disease/diagnostic imaging/metabolism/pathology ; Middle Aged ; Aged, 80 and over ; Amyloid beta-Peptides/metabolism ; Cerebral Small Vessel Diseases/diagnostic imaging ; Neuropsychological Tests ; Atrophy ; *Brain/diagnostic imaging/pathology ; Aniline Compounds ; Cohort Studies ; },
abstract = {BACKGROUND AND OBJECTIVES: Cognitive impairment in older adults is influenced by coexisting β-amyloid (Aβ), tau, and cerebral small vessel disease (CSVD). Cerebral microbleeds (CMBs) are associated with Aβ and CSVD, but their role on tau-related neurodegeneration remains unclear. We investigated whether the CMBs modify tau-related disease progression.

METHODS: A longitudinal, prospective cohort study was conducted involving participants with mild cognitive impairment, Alzheimer disease dementia from the memory disorder clinic of the single tertiary center, or cognitively unimpaired from the community. All participants underwent cognitive assessment, MRI, [18]F-flutemetamol PET for Aβ, and [18]F-MK-6240 PET for tau at baseline. Cognitive tests were performed annually and MRI at 2 years. Cognitive decline was defined by score changes over this period and cortical atrophy as annual cortical thickness change. Linear regression analyses were conducted after stratifying by total or lobar CMB presence.

RESULTS: Among the 201 participants (mean age 71.3 ± 7.0 years, 66.7% female), 95 had CMBs and 106 did not. Baseline Aβ or tau burden did not significantly differ between the 2 groups while white matter hyperintensity volume and lacunes were greater in the CMB group. Cross-sectionally, greater tau burden correlated with worse cognition, as measured by the Clinical Dementia Rating Scale Sum of Boxes (CDR-SOB) or Mini-Mental State Examination (MMSE) in both groups. Longitudinally, baseline tau burden was associated with CDR-SOB progression in the non-CMB group (β = 1.558, SE = 0.249, p < 0.001), but not in the CMB group (β = -0.031, SE = 0.405, p = 0.940; p-for-interaction = 0.001). Similar group differences were found for MMSE changes (non-CMB: β = -2.365, SE = 0.566, p < 0.001; CMB: β = -0.816, SE = 0.653, p = 0.217; p-for-interaction = 0.073). Stratification by lobar CMBs confirmed significant interaction effects for both CDR-SOB (p-for-interaction = 0.007) and MMSE (p-for-interaction = 0.045) scores. Imaging analysis showed more extensive cortical atrophy in the CMB group, but tau-related cortical atrophy was widespread only in the non-CMB group and minimal in the CMB group.

DISCUSSION: In the non-CMB group, tau burden was strongly associated with cognitive decline and cortical atrophy. By contrast, the CMB group exhibited greater CSVD burden and pronounced neurodegeneration not explained by tau, suggesting that additional mechanisms such as CSVD related to cerebral amyloid angiopathy or neuroinflammation may contribute to disease progression in this group.},
}

Humans
Female
Aged
Male
*Cerebral Hemorrhage/diagnostic imaging/complications/metabolism/pathology/psychology
*Cognitive Dysfunction/diagnostic imaging/metabolism/pathology/psychology
*tau Proteins/metabolism
Magnetic Resonance Imaging
Longitudinal Studies
Positron-Emission Tomography
Disease Progression
Prospective Studies
*Alzheimer Disease/diagnostic imaging/metabolism/pathology
Middle Aged
Aged, 80 and over
Amyloid beta-Peptides/metabolism
Cerebral Small Vessel Diseases/diagnostic imaging
Neuropsychological Tests
Atrophy
*Brain/diagnostic imaging/pathology
Aniline Compounds
Cohort Studies

@article {pmid41348997,
year = {2026},
author = {Conti, M and Mascioli, D and Simonetta, C and Ferrari, V and Bissacco, J and Bagetta, S and Carparelli, F and Bernardini, S and Di Giuliano, F and Marchionni, E and Pierantozzi, M and Mercuri, NB and Schirinzi, T and Stefani, A},
title = {Clinical, Biological, and Functional Connectivity Profile of Patients With De Novo Parkinson Disease Who Are APOE ε4 Carriers.},
journal = {Neurology},
volume = {106},
number = {1},
pages = {e214449},
doi = {10.1212/WNL.0000000000214449},
pmid = {41348997},
issn = {1526-632X},
mesh = {Humans ; *Parkinson Disease/genetics/physiopathology/cerebrospinal fluid ; Female ; Male ; *Apolipoprotein E4/genetics ; Cross-Sectional Studies ; Middle Aged ; Aged ; Heterozygote ; Amyloid beta-Peptides/cerebrospinal fluid ; tau Proteins/cerebrospinal fluid ; Electroencephalography ; *Brain/physiopathology ; },
abstract = {BACKGROUND AND OBJECTIVES: Growing evidence suggests that the APOE ε4 allele, a genetic risk factor for Alzheimer disease (AD), influences the clinical-pathologic features of Parkinson disease (PD). APOE ε4 promotes brain amyloid accumulation, indicating a PD subtype more susceptible to late copathology. However, the early correlates of APOE ε4 carriers in PD are not known. In this study, we used a multimodal approach to define the clinical, neurochemical, and neurophysiologic profiles of APOE ε4 carriers in PD at onset.

METHODS: We conducted a single-center, cross-sectional study at Tor Vergata Hospital (Rome, Italy), enrolling newly diagnosed, drug-naïve PD participants and age-matched/sex-matched healthy controls (HCs). Patients with PD were stratified by APOE genotype into ε4 and non-ε4 carriers and evaluated through a comprehensive clinical assessment and the measurement of CSF amyloid peptides and tau protein levels. Group differences in high-density EEG-based functional connectivity (FC) were analyzed using network-based statistics to identify APOE ε4-modulated patterns. Clinical and biomarker associations with network metrics were tested using analysis of covariance and correlation analyses.

RESULTS: The study included 66 PD participants (mean age 63.2 [10.1] years, 35% female, 52 ε4 noncarriers, 14 ε4 carriers) and 55 HCs (mean age 62.0 [15.2] years, 42% female). PD ε4, compared with PD non-ε4, demonstrated higher motor impairment, especially in bradykinesia (16.4 [7.6] vs 11.0 [5.6], p = 0.02) and gait disturbances (3.46 [2.23] vs 1.94 [1.46], p = 0.003) Movement Disorder Society-sponsored Unified Parkinson's Disease Rating Scale part III scores, and reduced CSF amyloid-β42 (Aβ42)/amyloid-β40 (Aβ40) ratio (0.09 [0.03] vs 0.13 [0.03], p < 0.001). Network analyses identified ε4-related FC alterations: decreased α-band connectivity (F = 3.9, p = 0.034) and increased β-band connectivity (F = 9.8, p < 0.001). In ε4 carriers, α-FC correlated inversely with gait disturbances (r = -0.62, p = 0.02) and positively with Montreal Cognitive Assessment (r = 0.57, p = 0.03) and CSF Aβ42/Aβ40 (r = 0.54, p = 0.04). β-FC correlated with bradykinesia in both groups, with stronger associations in ε4 carriers (r = 0.54, p = 0.04) than in non-ε4 (r = 0.28, p = 0.04).

DISCUSSION: APOE ε4 defines a PD subtype characterized by greater motor impairment, reduced CSF Aβ42/Aβ40, and distinct FC abnormalities since the onset. An early amyloid-mediated network disruption thus emerges as the potential biological signature of ε4 carriers. Although limited by single-center and cross-sectional design, this study supports APOE ε4 as a stratification marker for early diagnostic and therapeutic strategies in PD.},
}

Humans
*Parkinson Disease/genetics/physiopathology/cerebrospinal fluid
Female
Male
*Apolipoprotein E4/genetics
Cross-Sectional Studies
Middle Aged
Aged
Heterozygote
Amyloid beta-Peptides/cerebrospinal fluid
tau Proteins/cerebrospinal fluid
Electroencephalography
*Brain/physiopathology

@article {pmid41348991,
year = {2025},
author = {Hu, M and Li, A and Fleming, P and Gralla, J and Negrón Terón, K and Zhou, Y and Miller, EJ and Beyett, TS and Wen, Z and Du, Y and Fu, H and Ivanov, AA},
title = {Non-Catalytic Inhibitors of the p38/MK2 Interface: Repurposing Approved Drugs to Target Neuroinflammation in Alzheimer's Disease.},
journal = {Journal of medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.jmedchem.5c01425},
pmid = {41348991},
issn = {1520-4804},
abstract = {Neuroinflammation is a key driver of Alzheimer's disease and an emerging therapeutic target. The p38/MK2 pathway regulates microglial cytokine production, yet previous attempts have not yielded modulators with clinically suitable properties. Here, we apply an integrative structure-guided and screening strategy to identify small-molecule disruptors of the p38/MK2 protein-protein interaction (PPI). Virtual screening of FDA-approved drugs prioritized nilotinib, a BCR-ABL inhibitor, as a putative PPI disruptor. Biochemical and molecular dynamics analyses confirmed that nilotinib binds to p38, blocks MK2 association, and suppresses cytokine release in microglia. Guided by these findings, we developed a lysate-based TR-FRET ultrahigh-throughput assay that identified additional inhibitors, including α1-adrenergic antagonists doxazosin, terazosin, and alfuzosin. These compounds suppressed cytokine induction via docking groove blockade. Together, these results establish a non-ATP-competitive approach for selectively targeting the p38/MK2 complex and highlight the translational potential of drug repurposing to modulate neuroinflammation in Alzheimer's disease.},
}

@article {pmid41348702,
year = {2025},
author = {Wang, X and Wen, K and Li, Y and He, Y and Shen, W and Wang, H},
title = {Trends and Future Projections of Neurological Disorder Burden in Europe,1990-2021: Latest Insights from the GBD 2021 Study.},
journal = {Neuroepidemiology},
volume = {},
number = {},
pages = {1-19},
doi = {10.1159/000549912},
pmid = {41348702},
issn = {1423-0208},
abstract = {BACKGROUND: The systematic assessment of the burden of common neurological disorders in Europe based on latest epidemiological data remains lacking.

METHODS: We extracted data on disability-adjusted life years (DALYs), mortality, prevalence, and incidence of neurological disorders from the Global Burden of Disease 2021 study from 1990 to 2021. Future trends over the next 15 years were projected using autoregressive integrated moving average modeling.

RESULTS: In 2021, the age-standardized DALYs rates (ASDRs) of neurological disorders in Europe (1,502.3/100,000 population) was significantly higher than the global average (1,385.1/100,000 population). Among them, the ASDRs in Western Europe (1,584.23/100,000 population) was notably higher than that in Central Europe (1,354.65/100,000 population) and Eastern Europe (1,375.03/100,000 population). Ischemic stroke (31.98%) and Alzheimer's disease (20.24%) were the major contributors to the disease burden in Europe. Age-stratified analysis revealed that the elderly population(≥65 years old) bore the burden of stroke and Alzheimer's disease and other dementia. The overall disease burden was higher in females. From 1990 to 2021, data indicated a significant decline in the disease burden of ischemic stroke, Alzheimer's disease and other dementias, encephalitis, idiopathic epilepsy, intracerebral hemorrhage, and meningitis. Conversely, Parkinson's disease and other neurological disorders showed an upward trend. ARIMA forecast analysis suggested that from 2021 to 2036, the predicted ASDRs for Neurological disorders would be lower compared to previous levels.

CONCLUSION: Neurological disorders impose a greater burden in Europe than globally, primarily driven by ischemic stroke and Alzheimer's disease, with Western Europe, elderly, and female populations being disproportionately affected.},
}

@article {pmid41348686,
year = {2025},
author = {Zhou, Y and Huang, Y and Fan, Y and Xue, F},
title = {Co-regulation of microglial subgroups in Alzheimer's amyloid pathology: Implications for diagnosis and drug development.},
journal = {PloS one},
volume = {20},
number = {12},
pages = {e0337741},
doi = {10.1371/journal.pone.0337741},
pmid = {41348686},
issn = {1932-6203},
mesh = {*Microglia/metabolism/pathology ; *Alzheimer Disease/diagnosis/pathology/metabolism/drug therapy/genetics ; Animals ; Humans ; Receptors, Immunologic/metabolism/genetics ; Membrane Glycoproteins/metabolism/genetics ; Drug Development ; Mice ; Signal Transduction ; Cytokines/metabolism ; Transcriptome ; Male ; Neuroinflammatory Diseases ; Amyloid beta-Peptides/metabolism ; Gene Expression Regulation ; },
abstract = {Alzheimer's Disease (AD) is a progressive neurodegenerative disorder and the leading cause of dementia. Neuroinflammation drives AD progression and therefore represents a promising target for diagnosis and therapy. In early AD, microglia polarize into pro-inflammatory and anti-inflammatory cellular subgroups that mediate the initial immune response, yet the regulatory relationships between these microglial subgroups remain poorly understood. In this study, we investigated the interplay between pro- and anti-inflammatory microglial subgroups from multiple perspectives. Comparative transcriptomics and bioinformatics analyses implicated the Trem2 signaling pathway in an anti-inflammatory microglial subgroup. Fluorescence-activated cell sorting (FACS) and gene regulation analysis indicated that microglial subgrouping and microgliosis preceded cytokine upregulation during early amyloid pathology. Further immunoassays revealed that anti-inflammatory Neurodegeneration-Related Modules and pro-inflammatory microglial subgroups, Interferon-Related Modules and LPS-Related Modules, were co-regulated by shared upstream pro-inflammatory regulators. Such co-regulation of heterogeneous microglial subgroups may balance microglial activation and promote the development of AD chronic neuroinflammation. In summary, our study uncovered previously overlooked co-regulation of microglial subgroups in AD and provides a systems biology framework that may inform improved diagnostic markers and immunotherapeutic strategies.},
}

*Microglia/metabolism/pathology
*Alzheimer Disease/diagnosis/pathology/metabolism/drug therapy/genetics
Animals
Humans
Receptors, Immunologic/metabolism/genetics
Membrane Glycoproteins/metabolism/genetics
Drug Development
Mice
Signal Transduction
Cytokines/metabolism
Transcriptome
Male
Neuroinflammatory Diseases
Amyloid beta-Peptides/metabolism
Gene Expression Regulation

@article {pmid41348604,
year = {2025},
author = {Svinin, G and Glaab, E},
title = {Causal network analysis of omics data using prior knowledge databases.},
journal = {Briefings in bioinformatics},
volume = {26},
number = {6},
pages = {},
doi = {10.1093/bib/bbaf654},
pmid = {41348604},
issn = {1477-4054},
support = {C24/BM/18865990/AsynIntact//Luxembourg National Research Fund/ ; INTER/JPND23/17999421/AD-PLCG2//Luxembourg National Research Fund/ ; INTER/22/17104370/RECAST//Luxembourg National Research Fund/ ; INTER/EJP RD22/17027921/PreDYT//Luxembourg National Research Fund/ ; },
mesh = {Humans ; *Computational Biology/methods ; *Genomics/methods ; *Gene Regulatory Networks ; *Databases, Factual ; Databases, Genetic ; },
abstract = {Identifying causal relationships in omics data is essential for understanding underlying biological processes. However, detecting these relationships remains challenging due to the complexity of molecular networks and observational data limitations. To guide researchers, we conducted a systematic literature review of data-driven causal omics analysis methods that use structured prior knowledge from regulatory and interaction databases. We grouped methods into three approaches based on the extent of prior knowledge integration: regulon-level (direct regulator-target links, straightforward interpretation, but with the risk of oversimplification), flow-level (multi-step propagation from regulators to targets, broader mechanism explanation, but lacking uncertainty modeling), and network-level (system-wide interactions and crosstalk, most comprehensive, but with increased computational complexity and requiring particularly careful interpretation). These methods have demonstrated utility across diverse applications, including identification of therapeutic targets in acute myeloid leukemia, elucidation of mechanisms in IgA nephropathy, and detection of regulatory perturbations in Alzheimer's disease. We discuss the strengths, limitations, and representative use cases of each approach, and address general limitations and outline future research directions. This review serves as a practical guide for the entire analysis process, from selecting prior knowledge databases (PKDBs) to choosing and applying causal analysis methods for different research questions.},
}

Humans
*Computational Biology/methods
*Genomics/methods
*Gene Regulatory Networks
*Databases, Factual
Databases, Genetic

@article {pmid41348517,
year = {2025},
author = {Orfila, F and Leiva-Bañuelos, N and Vázquez-Ibar, O and Molloy, DW and O'Caoimh, R},
title = {Validity of the Spanish version of the quick mild cognitive impairment screen (Qmci-S).},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251400791},
doi = {10.1177/13872877251400791},
pmid = {41348517},
issn = {1875-8908},
abstract = {BackgroundAccurate, short, cognitive screening instruments are important for identifying mild cognitive impairment (MCI) and dementia including Alzheimer's disease. The Quick Mild Cognitive Impairment (Qmci) screen, given its brevity, may be useful in this setting but it has not been validated in Spanish.ObjectiveTo compare the diagnostic accuracy of the Spanish version (Qmci-S) to the Montreal Cognitive Assessment (MoCA).MethodsPatients aged ≥55 years were recruited from six Primary Care Teams in Barcelona, Spain, between 2018-2019. Dementia, MCI, and normal cognition (NC) were classified following neuropsychological testing, independent of the Qmci-S and MoCA scores. Diagnostic accuracy was determined by the area under receiver operating characteristic curves (AUC), adjusted for age and education.ResultsIn total, 337 patients were included, mean 77.9 years, standard deviation (SD) ± 6.9. Most were female (57.3%). The intraclass correlation coefficient for the Qmci-S was excellent (0.98). The Qmci-S had good to excellent diagnostic accuracy for separating NC from MCI and dementia (AUC 0.91) and was statistically greater than the MoCA (AUC 0.86), p = 0.029. Accuracy was similar for differentiating NC from MCI and MCI from dementia. The Qmci-S had a shorter administer time, mean 8.6 (±3.2) versus 12.75 (SD ±5.5) minutes, respectively, p < 0.001.ConclusionsThe newly developed Qmci-S screen showed excellent criterion, construct and concurrent validity versus the widely used MoCA and had statistically similar, good to excellent, diagnostic accuracy for cognitive impairment. Its significantly shorter administration time suggests it may be the better screen in a Spanish speaking population in primary care, though further research is required.},
}

@article {pmid41348458,
year = {2025},
author = {Das, B and Mukherjee, PK and Thorat, SS and Maharaj, V and Bodede, O and Khorommbi, NK and Matsabisa, MG},
title = {Therapeutic and Safety Evaluation of Enhydra fluctuans Lour. and Ipomoea aquatica Forssk. as Acetylcholinesterase, Butyrylcholinesterase, β-Secretase, and CytochromeP450 Inhibitors Using In Vitro and UPLC-QTOF-MS-Based Molecular Docking and Dynamic Simulation Study.},
journal = {Chemistry & biodiversity},
volume = {},
number = {},
pages = {e01969},
doi = {10.1002/cbdv.202501969},
pmid = {41348458},
issn = {1612-1880},
abstract = {Considering the multi-targeted drug approach, Enhydra fluctuans and Ipomoea aquatica were comprehensively investigated for their acetylcholinesterase, butyrylcholinesterase, and β-secretase enzyme inhibitory potential, which are linked to Alzheimer's disease. The results showed that I. aquatica produced more prominent anti-cholinesterase potential compared to E. fluctuans. But E. fluctuans showed more potent BACE1 inhibitory potential compared to I. aquatica. For the safety study, the extracts were tested for heavy metal content estimation, CYP450 isozyme inhibitory potential, and cytotoxicity in human hepatocellular carcinoma cells. Antioxidant capacity, total phenolics, and total flavonoids were significantly correlated with the anti-cholinesterase activity, where I. aquatica showed more protuberant potential compared to E. fluctuans. The UPLC-QTOF-MS analysis tentatively identified phytometabolites from the phenylethanoid glycosides and chlorogenic acids class in both the extracts. Further, in silico toxicity prediction, molecular docking, and dynamic simulation studies provided additional evidence on the safety profile and interaction potential of phytometabolites with AChE, BChE, and BACE1 enzymes.},
}

@article {pmid41348440,
year = {2025},
author = {Yu, J and Cho, JH and Han, K and Park, YM and Lee, SH},
title = {Reproductive Lifespan and Reproductive Factors in Relation to Dementia Risk in Postmenopausal Women With Type 2 Diabetes.},
journal = {Diabetes care},
volume = {},
number = {},
pages = {},
doi = {10.2337/dc25-1961},
pmid = {41348440},
issn = {1935-5548},
abstract = {OBJECTIVE: Endogenous estrogen exposure has been linked to a reduced risk of cognitive decline. Our study examined the influence of reproductive factors on the risk of dementia among women with diabetes.

RESEARCH DESIGN AND METHODS: We identified 159,751 postmenopausal women with type 2 diabetes aged over 40 years who underwent health examinations in 2009 from the National Health Information Database. Data on reproductive factors were obtained using self-administered questionnaires. Incident dementia was determined by diagnosis codes and records of antidementia medication prescriptions. Cox proportional hazards regression analyses estimated the risk of all-cause dementia, Alzheimer disease, and vascular dementia according to reproductive factors such as reproductive lifespan, parity, and hormone replacement therapy (HRT) use.

RESULTS: The mean age was 64.5 ± 8.0 years, and the mean reproductive lifespan was 33.6 ± 4.5 years. Over a median follow-up of 8.3 years, 24,218 cases of all-cause dementia were identified (18,819 cases of Alzheimer disease, 2,743 cases of vascular dementia). Compared with a reproductive lifespan of <30 years, ≥40 years was associated with lower risk of all-cause dementia (hazard ratio 0.73; 95% CI 0.69-0.78). Women with parity 1 had a 27% lower risk of all-cause dementia compared with women with parity 0, and women who used HRT for more than 5 years had a 17% lower risk compared with those who did not use HRT. Comparable effects were found for both Alzheimer disease and vascular dementia.

CONCLUSIONS: A longer reproductive lifespan was linked to a reduced risk of dementia in postmenopausal women with type 2 diabetes.},
}

@article {pmid41348342,
year = {2025},
author = {Rubin, R},
title = {Alzheimer Disease Blood Test Cleared for Primary Care, but Questions Remain About Its Use.},
journal = {JAMA},
volume = {},
number = {},
pages = {},
doi = {10.1001/jama.2025.21573},
pmid = {41348342},
issn = {1538-3598},
}

@article {pmid41348284,
year = {2025},
author = {Lee, W and Ma, X and Lee, S},
title = {The immuno-neurological axis: association between autoimmune diseases and dementia risk.},
journal = {GeroScience},
volume = {},
number = {},
pages = {},
pmid = {41348284},
issn = {2509-2723},
abstract = {Dementia is a growing global public health concern, with an increasing number of individuals affected due to the aging population. Although chronic inflammation is implicated in cognitive impairment, studies on its association with autoimmune diseases, which are representative chronic inflammatory diseases, are lacking. This study aimed to investigate whether the onset of autoimmune diseases is associated with an increased risk of dementia or cognitive impairment. This study used data from the Korean National Health Insurance Service-Health Screening from 2002 to 2019, with 8,743,801 person-years. The risk of dementia according to the type of autoimmune disease was calculated using the Cox proportional hazards model. The status and risk of cognitive impairment, which were assessed using the Korean Dementia Screening Questionnaire-Prescreening related with autoimmune diseases also estimated. Among participants, 8.3% developed dementia. All autoimmune diseases significantly increased dementia risk (hazard ratio [HR] 1.32; 95% confidence interval [CI] 1.29-1.35), particularly Alzheimer's disease (HR 1.36; 95% CI, 1.32-1.40), vascular dementia (HR, 1.21; 95% CI, 1.12-1.30), and unspecified dementia (HR, 1.25; 95% CI, 1.18-1.33). Autoimmune diseases also increased the risk of positive dementia screening (odds ratio [OR], 1.18; 95% CI, 1.12-1.24), particularly connective tissue disorders (OR, 1.24; 95% CI, 1.15-1.34). This large-scale cohort study demonstrates a significant association between autoimmune diseases and increased risk of dementia and cognitive impairment. These findings underscore the potential importance of chronic inflammation in dementia pathogenesis and highlight the need for early cognitive screening and intervention strategies in patients with autoimmune diseases.},
}

@article {pmid41348113,
year = {2025},
author = {Varshney, A and Rajput, A and Pokharkar, V},
title = {Formulation and characterization of lutein laden gel via nasal delivery: nasal permeation, and pharmacokinetic studies.},
journal = {Therapeutic delivery},
volume = {},
number = {},
pages = {1-16},
doi = {10.1080/20415990.2025.2598146},
pmid = {41348113},
issn = {2041-6008},
abstract = {AIM: Lutein exhibits poor aqueous solubility, chemical instability, and low bioavailability following oral administration, which restricts its therapeutic use in Alzheimer's disease (AD). Hence, a lutein-laden liposomal in situ gel was formulated to enhance bioavailability and brain targeting via nasal delivery.

METHOD: Lutein-laden liposomes were fabricated using an ethanol injection method and studied for various parameters.

RESULT AND CONCLUSIONS: The formulated lutein-laden liposomes showed a particle size, polydispersity index, and encapsulation efficiency of 71.8 ± 6.4 nm, 0.327 ± 0.007, and 95.59 ± 3.03%, respectively. The permeation studies on goat nasal mucosa revealed drug permeation from the lutein-laden liposomal in situ gel and fivefold higher permeation than the lutein solution-based in situ gel. The drug targeting efficiency of the developed formulation was 372.80%. The pharmacokinetic study of the developed formulation administered via the nasal route showed a twofold higher Cmax and a 1.7-fold higher AUC than the drug suspension administered via the oral route. The histopathological analysis indicated that the developed formulation was safe. Thus, intranasal delivery of lutein could surpass poor oral bioavailability and be studied for managing AD and its symptoms using an intranasal delivery-based brain-targeted approach.},
}

@article {pmid41347369,
year = {2025},
author = {Yang, J and Deng, Y and Qin, S and Chen, Z and Lu, Y and Ji, S and Hang, T and Song, M},
title = {An aggregation-induced emission-active theranostic agent for selectively detecting and intervening pathological Tau protein.},
journal = {Journal of materials chemistry. B},
volume = {},
number = {},
pages = {},
doi = {10.1039/d5tb01783a},
pmid = {41347369},
issn = {2050-7518},
abstract = {The accumulation of Tau aggregates is commonly linked with various neurodegenerative diseases, such as Alzheimer's disease, Pick's disease, and corticobasal degeneration. Notwithstanding substantial investments in the development of clinical strategies for effective intervention, traditional design paradigms are predominantly confined to molecules featuring either a solitary function or single-dimensional mode of intervention, ignoring the necessity of personalized and precise medicine. Herein, we design and synthesize a dual-functional aggregation-induced emission-active agent to serve as both a fluorescent probe for the imaging of pathological Tau and a modulator for intervention. This amphiphilic theranostic agent, named TPE-P9, is prepared via a one-pot Michael reaction between hydrophobic maleimide-modified tetraphenylethylene (TPE-Mal) and a hydrophilic cysteine-modified Tau-targeting peptide (CKVQIINKK). Microscale thermophoresis measurement and in vitro fluorescence analysis demonstrate that TPE-P9 exhibits specific binding affinity (Kd = 4.46 µM) and high selectivity towards Tau fibrils, featuring a pronounced low background interference, which is superior to the classical amyloid protein probe thioflavin T (ThT). At the living cellular level, TPE-P9 is capable of readily imaging endogenic pathological Tau to distinguish normal neurons from the lesional neurons in situ, and the staining consequence is almost consistent with that of ThT. On the other hand, as a modulator, TPE-P9 can potently protect neurons from cytotoxic Tau-induced apoptosis both by inhibiting aberrant post-translational modification-induced Tau self-assembly and by blocking the produced pathological Tau propagation, enhancing cell viability by 35.4%. These findings offer valuable insights for the development of innovative image-guided therapeutic strategies for targeted tauopathies treatment.},
}

@article {pmid41347325,
year = {2025},
author = {Li, J and Liu, J and Zhou, M and Xu, J and Xiao, Y and Fan, X and Xu, W},
title = {Decabromodiphenyl ethane as a neurotoxicant in Alzheimer's disease: unraveling its mechanisms through the integration of multiple computational toxicology methods.},
journal = {Drug and chemical toxicology},
volume = {},
number = {},
pages = {1-15},
doi = {10.1080/01480545.2025.2592931},
pmid = {41347325},
issn = {1525-6014},
abstract = {The role of environmental pollutants as risk factors for Alzheimer's disease (AD) and related neurodegenerative pathologies necessitates mechanistic investigation. Evidence implicates brominated flame retardants (BFRs)-decabromodiphenyl ethane (DBDPE)-in AD pathogenesis, though their molecular mechanisms remain inadequately elucidated. To address this challenge, we combined multiple cross-disciplinary methods (network toxicology, machine learning [ML], molecular docking, molecular dynamics [MD] simulations, and Mendelian randomization [MR] analysis) to systematically delineate DBDPE-induced AD pathogenesis. Initial screening of the SwissTargetPrediction database and GSE132903 dataset identified 47 overlapping DBDPE-AD targets. Subsequent protein-protein interaction (PPI) network analysis refined these to 42 high-confidence targets. Subsequently, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses revealed association of core targets with metabolic pathways and neuroactive ligand-receptor interactions. Three core targets were prioritized using ML framework. Molecular docking confirmed strong binding affinities between DBDPE and the core targets. Given PLAU's exceptional binding energy, we conducted MD simulations to validate complex stability and characterize binding-site interactions. Finally, MR analysis established causal links between PLAU and AD susceptibility. In summary, this study establishes a comprehensive theoretical framework for understanding the molecular mechanisms of DBDPE-induced AD and provides valuable insights for developing preventive and therapeutic strategies targeting AD associated with DBDPE exposure.},
}

@article {pmid41347112,
year = {2026},
author = {Huang, S and Zhong, L and Shi, Y},
title = {Multistage Alignment and Fusion for Multimodal Multiclass Alzheimer's Disease Diagnosis.},
journal = {Medical image computing and computer-assisted intervention : MICCAI ... International Conference on Medical Image Computing and Computer-Assisted Intervention},
volume = {15974},
number = {},
pages = {375-385},
pmid = {41347112},
abstract = {For the early diagnosis of Alzheimer's disease (AD), it is essential that we have effective multiclass classification methods that can distinct subjects with mild cognitive impairment (MCI) from cognitively normal (CN) subjects and AD patients. However, significant overlaps of biomarker distributions among these groups make this a difficult task. In this work, we propose a novel framework for multi-modal, multiclass AD diagnosis that can integrate information from diverse and complex modalities to resolve ambiguity among the disease groups and hence enhance classification performances. More specifically, our approach integrates T1-weighted MRI, tau PET, fiber orientation distribution (FOD) from diffusion MRI (dMRI), and Montreal Cognitive Assessment (MoCA) scores to classify subjects into AD, MCI, and CN groups. We introduce a Swin-FOD model to extract order-balanced features from FOD and use contrastive learning to align MRI and PET features. These aligned features and MoCA scores are then processed with a Tabular Prior-data Fitted In-context Learning (TabPFN) method, which selects model parameters based on the alignment between input data and prior data during pre-training, eliminating the need for additional training or fine-tuning. Evaluated on the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset (n = 1147), our model achieved a diagnosis accuracy of 73.21%, outperforming all comparison models (n = 10). We also performed Shapley analysis and quantitatively evaluated the essential contributions of each modality.},
}

@article {pmid41346856,
year = {2025},
author = {Yata, VK and Das, OP and Dansana, J and Gadtya, A and Meher, BR and Bukke, SPN and Kolliputi, N},
title = {Designing novel peptides with amyloid-β binding and clearance potential using BiLSTM and molecular dynamics.},
journal = {Frontiers in artificial intelligence},
volume = {8},
number = {},
pages = {1709505},
pmid = {41346856},
issn = {2624-8212},
abstract = {Generative artificial intelligence is transforming de novo biomolecular design, yet developing models that reliably generate functional, target-specific peptides remains a significant challenge. Here, we introduce and validate a novel two-stage Bidirectional Long Short-Term Memory (BiLSTM) framework for the generative design of short, functional peptides. Our AI pipeline is trained on full-length proteins annotated with specific Gene Ontology (GO) terms related to amyloid-β (Aβ) interaction and is fine-tuned on experimentally validated peptide fragments to capture local functional motifs within a global protein context. As a proof-of-concept, we applied this framework to generate peptides targeting Aβ42, a key pathological agent in Alzheimer's disease. From 1,000 AI-generated sequences, 25 candidates were shortlisted using biophysical filters (GRAVY, instability index, Shannon entropy), and 11 were prioritized via sequence similarity analysis, designated as AI-Designed Novel Peptides (ADNP1-ADNP11). Structural modeling (AlphaFold2) and docking (pyDockWEB) against Aβ42 identified ADNP7 as the top candidate, exhibiting a highly favorable docking score (-63.33 kcal/mol), with interactions localized to Aβ's aggregation-prone regions. All-atom molecular dynamics simulations (20 ns) confirmed complex stability, and MM/PBSA analysis yielded a strong binding free energy (-50.6 kcal/mol), driven primarily by hydrophobic and aromatic interactions involving PHE12 and TRP50 in ADNP7. This work demonstrates that our fine-tuned BiLSTM architecture can successfully generate novel, stable peptide sequences with high predicted binding affinity for a therapeutically relevant target. While the training data included proteins associated with Aβ clearance (GO:0097242), only binding interactions were computationally validated; clearance potential remains a hypothesis for future experimental testing. This study establishes a generalizable, AI-driven pipeline for functional peptide design, with broad applicability across therapeutic discovery and synthetic biology.},
}

@article {pmid41346812,
year = {2025},
author = {Mekulu, K and Aqlan, F and Yang, H},
title = {CharMark: character-level Markov modeling for interpretable linguistic biomarkers of cognitive decline.},
journal = {Frontiers in digital health},
volume = {7},
number = {},
pages = {1659366},
pmid = {41346812},
issn = {2673-253X},
abstract = {Dementia, one of the most prevalent neurodegenerative diseases, affects millions worldwide. Understanding linguistic markers of dementia is crucial for elucidating how cognitive decline manifests in speech patterns. Current non-invasive assessments like the Montreal Cognitive Assessment (MoCA) and Saint Louis University Mental Status (SLUMS) tests rely on manual interpretation and often lack detailed linguistic insight. This paper introduces a first-of-its-kind interpretable artificial intelligence (IAI) framework, CharMark, which leverages first-order Markov Chain models to characterize language production at the character level. By computing steady-state probabilities of character transitions in speech transcripts from individuals with dementia and healthy controls, we uncover distinctive character-usage patterns. The space character " ", representing pauses, (treated here as the space token between words rather than acoustic pauses), and letters such as "n" and "i" showed statistically significant differences between groups. Principal Component Analysis (PCA) revealed natural clustering aligned with cognitive status, while Kolmogorov-Smirnov tests confirmed distributional shifts. A Lasso Logistic Regression model further demonstrated that these character-level features possess strong discriminative potential. Our primary contribution is the identification and characterization of candidate linguistic biomarkers of cognitive decline; features that are both interpretable and easily computable. These findings highlight the potential of character-level modeling as a lightweight, scalable strategy for early-stage dementia screening, particularly in settings where more complex or audio-dependent models may be impractical.},
}

@article {pmid41346478,
year = {2025},
author = {Boyle, R and Dehghani, N and Emrani, S and Wadhwani, AR and Matyi, M and Cousins, KAQ and Rhodes, E and Nelson, B and Stites, SD and Xie, SX and Dratch, L and Van Deerlin, VM and Snyder, A and Irwin, DJ and McMillan, CT and Massimo, L},
title = {Higher neighborhood deprivation is associated with accelerated disease progression in behavioral-variant frontotemporal degeneration.},
journal = {Alzheimer's & dementia. Behavior & socioeconomics of aging},
volume = {1},
number = {4},
pages = {},
pmid = {41346478},
issn = {2997-3805},
abstract = {INTRODUCTION: Neighborhood deprivation is associated with shorter survival, cognitive impairment, and neurodegeneration in aging and Alzheimer's disease. However, the association of neighborhood deprivation with disease progression in behavioral-variant frontotemporal degeneration (bvFTD) is unknown.

METHODS: We examined associations between tertiles of neighborhood deprivation, using the Area Deprivation Index (ADI), and survival in 311 individuals clinically diagnosed with bvFTD from the Penn FTD Center. In a subset (n = 161) with complete baseline data across measures of global cognition, executive function, and language, we examined the association of ADI with longitudinal change.

RESULTS: Compared to adults living in the least deprived neighborhoods, those living in the most deprived neighborhoods showed shorter survival after symptom onset and faster decline in global cognition, executive and language functions, independent of genetic risk.

DISCUSSION: Living in more deprived neighborhoods was associated with an accelerated disease course in bvFTD, highlighting an important socioeconomic disparity in disease prognosis.

N/A.},
}

@article {pmid41346442,
year = {2025},
author = {Chen, YC and Chen, TB and Chen, HC},
title = {MRI-derived global small vessel disease burden serves as a marker of hippocampal sclerosis and clinical stage across the probable Alzheimer's disease continuum.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1692747},
pmid = {41346442},
issn = {1663-4365},
abstract = {INTRODUCTION: Cerebral small vessel disease (SVD) contributes to cognitive decline and hippocampal sclerosis (HS), yet its role across the Alzheimer's disease (AD) continuum remains incompletely understood. We aimed to determine whether composite MRI-based SVD scores serve as markers of cognitive impairment and HS in cognitively unimpaired (CU) individuals, patients with mild cognitive impairment (MCI), and those with probable AD dementia.

METHODS: We retrospectively analyzed 200 participants (24 CUs, 34 MCI, 142 AD) from the dementia registry at Kuang Tien General Hospital (January 2024-June 2025). SVD burden was quantified using three composite imaging scores: global SVD, cerebral amyloid angiopathy (CAA)-SVD, and hypertensive arteriopathy (HA)-SVD. Associations with cognitive performance, clinical staging, and HS were examined using multivariable regression models.

RESULTS: Global SVD and CAA-SVD scores correlated with Cognitive Abilities Screening Instrument (CASI) total and domain subscores, Clinical Dementia Rating (CDR) global score, and CDR sum of boxes (CDR-SB). Notably, only the global SVD score remained independently associated with both CDR-SB and HS after adjustment for relevant confounders.

DISCUSSION: MRI-derived global SVD burden, reflecting the combined effects of CAA and HA, is strongly associated with cognition, clinical staging, and HS across the probable AD continuum, supporting the global SVD score as a clinically useful biomarker of vascular contributions. Since MCI/AD diagnoses were based on clinical criteria without confirmation using cerebrospinal fluid or positive positron emission tomography biomarkers, potential misclassification may exist; findings should be interpreted with caution.},
}

@article {pmid41346439,
year = {2025},
author = {Cong, S and Wang, M and Yan, L and Sun, L and Zheng, B and Xie, J and Yu, T and Qian, Y},
title = {Correction: Current application status of non-invasive brain stimulation techniques in Alzheimer's disease: a bibliometric analysis.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1730649},
doi = {10.3389/fnagi.2025.1730649},
pmid = {41346439},
issn = {1663-4365},
abstract = {[This corrects the article DOI: 10.3389/fnagi.2025.1585885.].},
}

@article {pmid41346437,
year = {2025},
author = {Jain, S and Vohora, D},
title = {Decanoic acid, an MCT dietary component, alleviates cognitive impairment, cellular senescence, and promotes autophagy in accelerated aging and neurotoxic mouse models induced by chronic administration of D-galactose and D-galactose/AlCl3.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1676926},
pmid = {41346437},
issn = {1663-4365},
abstract = {INTRODUCTION: Cognitive decline advances with age, increasing the risk of dementia and Alzheimer's disease among older adults. Medium-chain triglyceride (MCT) ketogenic diets have shown potential in slowing down age-related cognitive decline; however, the exact neuroprotective roles of MCT components, specifically decanoic acid and octanoic acid, remain unclear.

METHODS: Swiss Albino mice were subjected to D-galactose to trigger accelerated aging, or to a combination of D-galactose and aluminium chloride to mimic Alzheimer's disease-like neurotoxicity. The animals received treated with decanoic acid, octanoic acid, or both. Cognitive function was assessed using the Morris water maze, while brain tissues were examined for oxidative stress markers, autophagy indicators, senescence activity, and amyloid-β levels.

RESULTS: Decanoic acid significantly improved learning and memory performance, enhanced antioxidant enzyme activity (superoxide dismutase, reduced glutathione, catalase), promoted autophagy by inhibiting mTOR, reduced cellular senescence (β-galactosidase-positive cells), and decreased amyloid-β toxicity. In contrast, octanoic acid showed no significant mechanistic effects, though it slightly improved cognitive behaviour.

DISCUSSION: This study demonstrates that decanoic acid, unlike octanoic acid, exhibits significant neuroprotective effects against accelerated aging and neurotoxicity, similar to Alzheimer's disease. These findings highlight the differences in the neuroprotective mechanisms of decanoic and octanoic acids, implying that MCT-based diets should be re-evaluated as a preventive strategy for cognitive decline and neurodegenerative diseases.},
}

@article {pmid41346255,
year = {2025},
author = {Rooprai, S and Dogra, H and Karimi, A and Rafique, R and D'Alessandro, E and Bearss, K and Robichaud, S and Bar, RJ and DeSouza, JF},
title = {Dancing through time: Cognitive changes over six years of community dance in Parkinson's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251393640},
doi = {10.1177/13872877251393640},
pmid = {41346255},
issn = {1875-8908},
abstract = {BackgroundParkinson's disease (PD) is the most common neurodegenerative disorder after Alzheimer's disease, and is characterized by motor and non-motor symptoms, including gait dysfunction and cognitive decline. Dance has emerged as a promising intervention for improving motor and non-motor symptoms in persons with PD (PwPD), yet long-term effects remain underexplored.ObjectiveTo assess changes in cognitive function and gait performance over six years among PwPD who participated in a weekly dance program, compared to a Reference group who remained physically inactive.MethodsThis six-year longitudinal observational study included 43 PwPD who attended weekly dance classes and were evaluated using the Mini-Mental State Examination (MMSE) and Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS). A Reference group of 28 PwPD, matched on age, gender, and Hoehn & Yahr scores, were selected from the Parkinson's Progression Marker Initiative, and assessed using the MDS-UPDRS and Montreal Cognitive Assessment (MoCA). Cognitive scores were standardized. Generalized estimating equations were used to compare cognitive and gait outcomes across time.ResultsThe Dance group was significantly different from the Reference group (p < 0.001), with improved cognitive scores in 2016, 2017, and 2018. The Dance group had worse gait at baseline, however, the Reference group showed significantly poorer gait performance by 2018. In a subset of our data (n=10), no significant association was found between gait and cognitive scores.ConclusionsAfter two years of weekly dance, the Dance group showed improvements in cognition and maintained stability in gait performance. The findings highlight the potential neuroprotective benefits of continued dance engagement over six years.},
}

@article {pmid41345983,
year = {2025},
author = {Abi-Ghanem, C and Opiela, AK and Paul, AS and Comito, ML and Hao, L and Martino, G and Kyaw, NR and Salinero, AE and Mansour, FM and Kelly, RD and Mutahi, AM and Sura, A and Thrasher, CA and Groom, EA and Batchelder, MR and Zuloaga, KL},
title = {Loss of ovarian hormones is detrimental in early disease stages of mouse models of Alzheimer's disease and multi-etiology dementia.},
journal = {Biology of sex differences},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13293-025-00795-4},
pmid = {41345983},
issn = {2042-6410},
support = {A2022001F//Bright-Focus Foundation/ ; 908878//American Heart Association/ ; 25PRE1374600//American Heart Association/ ; R01 NS110749/NS/NINDS NIH HHS/United States ; U01 AG072464/AG/NIA NIH HHS/United States ; AARG-21-849204/ALZ/Alzheimer's Association/United States ; },
abstract = {BACKGROUND: Up to 80% of Alzheimer's disease (AD) patients suffer from brain vascular damage resulting in multi-etiology dementia (MED). Sex is a well-known risk factor for dementia; out of three AD patients two are women. 17β-estradiol, a predominant ovarian hormone in woman before menopause, is known to have beneficial effects on the cerebrovasculature, neuroinflammation and neuroprotection. Here, we investigated the consequences of the loss of ovarian hormones caused by surgical menopause (ovariectomy) on AD and MED.

METHODS: The App[NL-F] knock-in mice were used to model AD. At about 5.5 months of age, a stage corresponding to early disease pathology, female App[NL-F] mice were subjected to ovariectomy (OVX) or sham surgery (Intact) and left to recover for 3 weeks to clear any endogenous gonadal hormones. In half of the mice from each group, MED was modeled using chronic cerebral hypoperfusion (unilateral carotid artery occlusion), a model of vascular contributions to cognitive impairment and dementia (VCID). Control animals (AD only model) received sham surgery. Mice were then subjected to a battery of behavioral tests before being euthanized and brains were collected to assess pathology.

RESULTS: We found that loss of ovarian hormones impairs spatial learning and memory, impairs activities of daily living, and affects underlying pathology including compromising microglial response. Some of these effects were exacerbated by cerebral hypoperfusion (VCID).

CONCLUSIONS: These results shed light on the effects of ovarian hormone loss after surgical menopause in female mouse model of AD and MED in order to better understand sex-specific risk factors.},
}

@article {pmid41345970,
year = {2025},
author = {Lehodey, A and Montagne, B and Rehel, S and Kaliman, P and Chocat, A and Mezenge, F and Landeau, B and de la Sayette, V and Chételat, G and Rauchs, G and Poisnel, G and , },
title = {Telomere dynamics are influenced by sleep, sleep variability and circadian rhythms in older adults with or without alzheimer's risk.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-025-01923-3},
pmid = {41345970},
issn = {1758-9193},
support = {667696//European Union's Horizon 2020 Research and Innovation Program/ ; 667696//European Union's Horizon 2020 Research and Innovation Program/ ; },
abstract = {INTRODUCTION: Sleep and circadian rhythm disturbances have been related to cognitive decline and increased risk of Alzheimer's disease (AD). These disruptions are also closely associated with biological ageing processes. Telomere shortening, a key marker of cellular ageing, has been implicated in various age-related diseases, including AD. Although sleep disturbances have been linked to shorter telomere length (TL), the effects of sleep, its variability, and circadian rhythms on telomere dynamics (over 18 months) remain unknown. Furthermore, the interplay between these factors and AD risk has yet to be investigated in healthy older adults. Therefore, the objective of this study was to explore how sleep, sleep variability, and circadian rhythms affect telomere dynamics in healthy older adults and the influence of AD risk on these relationships.

METHODS: Data from 124 healthy older adults (mean age ± SD: 69.27 ± 3.73y) from the Age-Well interventional trial (NCT02977819) were analyzed. Blood samples were collected to determine three TL metrics (50th and 20th percentile TL, and percentage of critically short telomeres (%CST) at baseline and after 18-month follow-up). Sleep and its variability were assessed using the Somno-Art[®] device over 5 nights (n = 77), and circadian rhythms using actigraphy for 1 week (n = 123). Multiple linear regressions examined whether baseline sleep and circadian rhythm measures predicted TL changes over time. Interaction analyses assessed the modulatory effects of amyloid (Aβ) status, assessed using Forbetapir-PET imaging, and APOE4 status on these relationships. Age, sex, education, BMI, and intervention group were included as covariates.

RESULTS: Poor sleep quality (characterized by lower sleep efficiency and higher wake after sleep onset) and greater variability in sleep efficiency predicted an increase in %CST. Greater regularity in sleep/wake patterns was associated with a decrease in 50th and 20th percentile TL and an increase in %CST. In Aβ-positive individuals, longer latency of rapid eye movement sleep predicted a reduction in 20th percentile TL and an increase in %CST.

CONCLUSIONS: This study suggests that poor sleep quality, sleep variability and circadian rhythm disturbances may accelerate cellular ageing through telomere shortening in older adults. Our results highlight the potential value of sleep interventions in mitigating biological ageing and reducing vulnerability to age-related diseases.},
}

@article {pmid41345807,
year = {2025},
author = {Lawrence, JM and Dampier, W and Mell, JC and De Souza, DR and Schardien, K and Yeakle, K and Barnett, RJ and Sen, B and Ahmed, A and Bouchard, M and Wigdahl, B and Nonnemacher, MR},
title = {Inflammatory microglia signals drive A1-like polarization of astrocytes even in the presence of HIV-1 Tat.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {251},
pmid = {41345807},
issn = {1559-1182},
support = {NS089435/NS/NINDS NIH HHS/United States ; MH079785/MH/NIMH NIH HHS/United States ; },
mesh = {*Astrocytes/metabolism/pathology/drug effects ; Humans ; *Microglia/metabolism/pathology/drug effects ; *tat Gene Products, Human Immunodeficiency Virus/metabolism/pharmacology ; *Inflammation/pathology/metabolism ; Blood-Brain Barrier/metabolism/pathology/drug effects ; *Signal Transduction/drug effects ; *Cell Polarity/drug effects ; *HIV-1/metabolism ; Endothelial Cells/metabolism/drug effects ; Cells, Cultured ; },
abstract = {In the context of neurodegeneration, activated microglia facilitate inflammation via secretion of TNF-α, IL-1α, and C1q. Astrocytes exposed to this signaling array polarize to a reactive inflammatory phenotype, termed A1 or A1-like. Astrocytes are essential for neuronal survival, synaptic support, and blood-brain barrier (BBB) function, but A1-like astrocytes upregulate inflammatory gene expression, downregulate neurotrophic factors, and secrete neurotoxic signals. The consequences of A1-like polarization on BBB function are unknown but may have etiological implications for some diseases. Frequently identified by upregulation of complement component 3 (C3), A1-like astrocytes have been characterized in neurodegenerative disorders like Alzheimer's disease, with polarization correlated with disease progression and severity. However, the role of A1-like astrocytes in neurodegeneration associated with chronic viral infections, like HIV-1-associated neurocognitive disorder (HAND), remains unclear. An in vitro system using primary human astrocytes, as well as a BBB model featuring primary human brain microvascular endothelial cells (BMECs) co-cultured with astrocytes, was used to elucidate cellular and molecular consequences of chronic astrocyte activation. As measured by whole transcriptome analysis and protein expression assays, repeated treatment with TNF-α, IL-1α, and C1q induced A1-like polarization of astrocytes both in monoculture and in a BBB model, resulting in increased secretion of pro-inflammatory signals. No substantial change to BBB permeability was observed. In contrast, exposure to HIV-1 viral protein Tat did not independently induce A1-like polarization. Ongoing investigations into the effect of astrocyte polarization on BBB integrity and treatment with pathogenic proteins may provide insights into the role of neurotoxic astrocytes in neurovirologic pathologies.},
}

*Astrocytes/metabolism/pathology/drug effects
Humans
*Microglia/metabolism/pathology/drug effects
*tat Gene Products, Human Immunodeficiency Virus/metabolism/pharmacology
*Inflammation/pathology/metabolism
Blood-Brain Barrier/metabolism/pathology/drug effects
*Signal Transduction/drug effects
*Cell Polarity/drug effects
*HIV-1/metabolism
Endothelial Cells/metabolism/drug effects
Cells, Cultured

@article {pmid41345718,
year = {2025},
author = {Platen, M and Gläser, E and Dahling, V and Gesell, D and Hauptmann, M and Horenkamp-Sonntag, D and Koller, D and Kubat, D and Marschall, U and Riederer, C and Scheibner, H and Schroth, J and Swart, E and Michalowsky, B},
title = {Regional disparities of antidementia drug treatment in Germany: what can we learn for the new generation of Alzheimer's therapies.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-025-01902-8},
pmid = {41345718},
issn = {1758-9193},
abstract = {BACKGROUND: Current antidementia drugs can temporarily slow cognitive decline in Alzheimer's disease but are underused. Regional and socioeconomic disparities, including limited specialist access in rural or deprived areas, may exacerbate inequities and challenge the rollout of emerging disease-modifying therapies. This study aimed to evaluate associations between regional contextual factors and antidementia drug prescription (AD-Rx) among newly diagnosed people living with Alzheimer's disease (PlwAD) in Germany and to identify spatial clustering of prescribing patterns.

METHODS: This study analyzed anonymized claims data from three statutory health insurers for 53,753 PlwAD who received their first diagnosis between January 2020 and December 2022. Regions, defined by three-digit postal codes (ZIP3, n = 576), were categorized by the German Index of Socioeconomic Deprivation (GISD) quintiles and Degree of Urbanization (urban, suburban, rural). Multilevel logistic regression with random intercepts for ZIP3 was used to assess associations between receiving AD-Rx (dichotomous) and urbanization and deprivation, adjusting for age, sex, the Charlson Comorbidity Index, the long-term care level and the year of diagnosis. Global Moran's I was used to evaluate large-scale spatial clustering, and regional Moran's I was calculated to detect regional hotspots and coldspots.

RESULTS: Overall, 64% of PlwAD received at least one AD-Rx. Rural residency was associated with slightly lower odds of receiving AD-Rx compared to urban areas (OR 0.92; 95%CI 0.87-0.98; p = 0.010), whereas deprivation was not. Interaction models demonstrated that an increased deprivation further reduced AD-Rx odds in rural areas (OR per GISD unit = 0.98; 95% CI 0.96-0.99; p = 0.024). Global Moran's I revealed no significant large-scale clustering (I = 0.011; p = 0.613), but regional analysis identified several regional hotspots (high-high clusters) predominantly in moderately deprived urban areas and coldspots (low-low clusters) in highly deprived or rural areas.

CONCLUSION: Alzheimer's patients in rural and high-deprivation regions face limited access to recommended antidementia medications. Targeted interventions, such as teleconsultations, expanding specialist outreach, and collaborative care models in underserved areas, as well as regional dementia networks and national registries, could promote the equitable delivery of current and future Alzheimer's antibody therapies. However, further qualitative and quantitative research is needed to identify the underlying regional causes of these treatment disparities.

TRIAL REGISTRATION: DRKS00031944.},
}

@article {pmid41345709,
year = {2025},
author = {Oosterlynck, M and Leroux, E and Namasivayam, B and Bouillet, T and Caillierez, R and Loyens, A and Mazur, D and Perbet, R and Lefebvre, C and Aboulouard, S and Maurage, CA and Accart, B and Buée, L and Colin, M},
title = {Stratification of brain-derived extracellular vesicles of Alzheimer's disease patients indicates a unique proteomic content and a higher seeding capacity of small extracellular vesicles.},
journal = {Translational neurodegeneration},
volume = {14},
number = {1},
pages = {63},
pmid = {41345709},
issn = {2047-9158},
mesh = {*Alzheimer Disease/metabolism/pathology ; *Extracellular Vesicles/metabolism/pathology ; Humans ; Proteomics/methods ; *Brain/metabolism/pathology ; Animals ; Male ; Female ; tau Proteins/metabolism ; Mice ; Aged ; Aged, 80 and over ; Mice, Transgenic ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is the most prominent form of dementia worldwide. It is characterized by tau lesions that spread throughout the brain in a spatio-temporal manner. This has led to the prion-like propagation hypothesis implicating a transfer of pathological tau seeds from cell to cell. Human brain-derived extracellular vesicles (BD-EVs) isolated from the brain-derived fluid of AD patients contain seeds that contribute to this tau pathology spreading. Knowing the rich diversity of EVs, isolation of functional EV sub-populations is required to unravel their implication in the pathophysiology of AD.

METHODS: Here, enriched-small EVs (eSEVs) and enriched-large EVs (eLEVs) were isolated from frozen tissues after collagenase enzymatic brain dissociation to guarantee the best EVs' integrity. Then proteomic profiling and tau seeding capacity testing were performed in vitro and in vivo.

RESULTS: BD-EVs were stratified according to their size (eSEVs and eLEVs) and characterized to define new markers specific to EVs in AD. Both AD-derived eSEVs and eLEVs show the presence of GWAS-associated proteins and indicate a specific AD pathophysiological signature. Notably, AD eSEVs contain more proteins relative to the integrin-mediated synaptic signaling, while AD eLEVs proteins were more related to respiratory electron transport and brain immunity. Injection of these vesicles in transgenic mouse brain revealed that the AD-derived eSEVs are more prone than eLEVs to participate in the prion-like propagation and hence represent an interesting therapeutic target.

CONCLUSION: This study highlights the significant contribution of AD-derived EVs to tau propagation and provides new insights into different roles of EV sub-populations in AD.},
}

*Alzheimer Disease/metabolism/pathology
*Extracellular Vesicles/metabolism/pathology
Humans
Proteomics/methods
*Brain/metabolism/pathology
Animals
Male
Female
tau Proteins/metabolism
Mice
Aged
Aged, 80 and over
Mice, Transgenic

@article {pmid41345651,
year = {2025},
author = {Liu, C and Xu, S and Yao, H and Wang, Y and Liu, Q and Zhou, H and Luo, Y and Li, X and Li, S and Li, C},
title = {SerpinA3N-APOE interaction in astrocytes exacerbates Alzheimer's disease progression through NFκB activation.},
journal = {Journal of neuroinflammation},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12974-025-03644-8},
pmid = {41345651},
issn = {1742-2094},
support = {2017YFE9126600//National Key R&D Program of China/ ; LD25H090001//Natural Science Foundation of Zhejiang Province/ ; 31830111//National Natural Science Foundation of China/ ; 32500630//National Natural Science Foundation of China/ ; 2019-01-07-00-07-E00040//Key Research and Innovation Program of Shanghai Municipal Education Commission/ ; },
abstract = {Alzheimer's disease (AD) is one of the most prevalent neurodegenerative disorders characterized by β-amyloid (Aβ) deposition, neurofibrillary tangles, neuronal loss, and neuroinflammation. It represents a growing global health crisis. Although astrocytes contribute to neuroinflammatory cascades, their molecular regulators in AD progression remains elusive. Here, through single-cell transcriptomic analysis, we identified SerpinA3N as a disease-progressive modulator upregulated in AD astrocytes, with expression levels correlating with pathological severity. Astrocytic SerpinA3N knockdown in AD mice rescued cognitive deficits across multiple behavioral tests, and concurrently attenuated neuroinflammatory responses, as evidenced by decreased astrocytic/microglial activation and reduced cytotoxic substance release. Moreover, histopathological analyses demonstrated decreased neuronal loss and Aβ deposition following SerpinA3N knockdown. Mechanistically, we elucidated that SerpinA3N cooperated with APOE to exacerbate AD pathology through NFκB signaling activation. Our study uncovers a novel astrocyte-mediated pathogenic cascade driving AD progression and establishes SerpinA3N as a promising therapeutic target for neuroinflammation modulation in AD.},
}

@article {pmid41345521,
year = {2025},
author = {Elnemais Fawzy, M and Wang, S and Palmer, P and Gatchel, J and Marshall, GA and Gagliardi, G and Vannini, P and , },
title = {Association between anosognosia and neuropsychiatric symptoms in Alzheimer's disease dementia patients.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-025-29569-z},
pmid = {41345521},
issn = {2045-2322},
support = {AG061083/NH/NIH HHS/United States ; },
abstract = {Anosognosia, the lack of awareness of memory decline, and Neuropsychiatric Symptoms (NPS) are prevalent and debilitating symptoms in Alzheimer's disease (AD) dementia. Understanding the coexistence of these symptoms may help guide clinical interventions and treatment strategies. This study aimed to compare NPS prevalence in patients with and without anosognosia at baseline and to assess the association between anosognosia and NPS over time. We examined patients with AD dementia enrolled in the Alzheimer's Disease Neuroimaging Initiative (ADNI). To be included in the current study, patients had to have undergone baseline assessments and at least one subsequent follow-up evaluation. Furthermore, all patients had to have amyloid (as assessed using Positron Emission Tomography, PET), Mini-Mental State Examination (MMSE), Neuropsychiatric Inventory (NPI), and Everyday Cognition (ECog) variables available throughout the study. Anosognosia, our exposure of interest, was determined using Ecog scores from patients and study partners. Study partners evaluated the presence or absence of 12 NPS (our outcomes of interest) using the NPI. Cox proportional hazards models, excluding patients who had any symptoms of NPS at baseline, were used to evaluate NPS onset by group (anosognosia/no anosognosia) while adjusting for age, sex, years of education, and MMSE. 112 patients with follow-up data (mean = 1 year) were included in this study. Of these, 47.3% (n = 53) had anosognosia, while 52.7% (n = 59) did not. In those with anosognosia at baseline, we observed a trend toward greater prevalence of agitation and motor symptoms. Exploratory time-to-event analysis demonstrated that the patients with anosognosia had a faster onset of apathy (HR: 2.78, 95% CI: 1.37-5.62, p = 0.01) compared to the patients without anosognosia. In this exploratory study, while there were no significant differences in frequency of NPS at baseline between the groups, patients with anosognosia demonstrated faster onset of apathy as compared to patients without anosognosia. These findings underscore the importance of longitudinal assessments and tailored interventions targeting the management of NPS in AD dementia patients with anosognosia. Further research is warranted to explain the underlying mechanisms driving these associations and to inform the development of targeted therapeutic strategies aimed at improving patient outcomes in this population.},
}

@article {pmid41345430,
year = {2025},
author = {Bekhet, S and Saad, N and Farag, S},
title = {Alzheimer disease predicting from clinical and MRI data using DeepALZNET dual pathway framework.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {43250},
pmid = {41345430},
issn = {2045-2322},
mesh = {*Alzheimer Disease/diagnostic imaging/diagnosis ; Humans ; *Magnetic Resonance Imaging/methods ; Neural Networks, Computer ; Brain/diagnostic imaging/pathology ; Aged ; Female ; Male ; Disease Progression ; Deep Learning ; },
abstract = {Alzheimer's Disease (AD) is a significant neurological condition characterized by progressive cognitive deterioration, with prevalence rising exponentially with age. Currently, there is no effective cure, and the disease progression impacts patients' quality of life, often leading to severe symptoms before death. The gradual development of AD symptoms, often mistaken for typical aging, frequently leads to delayed diagnosis. This underscores the critical need for precise, early diagnostic methodologies, as timely intervention plays a crucial role in managing progression. Accordingly, this paper introduces DeepALZNET, a dual-pathway computational framework designed to enhance AD prediction by offering two independent processing pathways: one for structured clinical data and another for unstructured brain MRI scans. The first pathway combines a 1D Convolutional Neural Network (CNN) with a Random Forest classifier to analyze clinical data, while the second employs a transfer-learning-based VGG19 architecture to detect subtle structural changes in MRI scans. Empirical validation on two publicly available datasets (2k clinical cases and 40k MRI images) demonstrated that both pathways achieved competitive accuracy ([Formula: see text]), with further evaluation on ADNI and OASIS benchmarks confirming robustness. Unlike recent transformer-based or attention-driven methods, which often demand large multimodal datasets and high computational resources, DeepALZNET prioritizes practical applicability, interpretability, and adaptability, operating effectively with either clinical or imaging data alone. This design bridges the gap between benchmark-driven research and deployable real-world solutions, with potential for multimodal fusion or attention integration in future work.},
}

*Alzheimer Disease/diagnostic imaging/diagnosis
Humans
*Magnetic Resonance Imaging/methods
Neural Networks, Computer
Brain/diagnostic imaging/pathology
Aged
Female
Male
Disease Progression
Deep Learning

@article {pmid41345289,
year = {2025},
author = {Bennis, K and Canal-Garcia, A and Pereira, JB and Volpe, G and Eustache, F and Phillips, C and Bastin, C and Collette, F and Vandewalle, G and Hinault, T},
title = {Diurnal dynamics of multilayer brain networks predict cognitive trajectories in aging.},
journal = {GeroScience},
volume = {},
number = {},
pages = {},
pmid = {41345289},
issn = {2509-2723},
support = {FRS-FNRS//Fonds De La Recherche Scientifique - FNRS/ ; FRSM 3.4516.11//Fonds De La Recherche Scientifique - FNRS/ ; F.4513.17//Fonds De La Recherche Scientifique - FNRS/ ; T.0242.19//Fonds De La Recherche Scientifique - FNRS/ ; EOS Project MEMODYN No. 30446199//Fonds De La Recherche Scientifique - FNRS/ ; Concerted Research Actions - SLEEPDEM 17/27-09//Fédération Wallonie-Bruxelles/ ; 15018//Stop Alzheimer Foundation/ ; 2019/0025//Stop Alzheimer Foundation/ ; ISS290//GE Healthcare Ltd (UK)/ ; 2022-01108//Swedish Research Council/ ; AF-968323//Swedish Alzheimer Foundation/ ; FO2022-0147//Swedish Brain Foundation/ ; 2020-01016//Gamla Tjänarinnor/ ; 2021-01207//Gamla Tjänarinnor/ ; 2022-01341//Gamla Tjänarinnor/ ; Contract no. 760250/28.12.2023//European Union - NextGenerationEU + Romanian Gov./ ; PNRR-C9-I8-CF109/31.07.2023//European Union - NextGenerationEU + Romanian Gov./ ; National Recovery Plan//Romanian Ministry of Research, Innovation and Digitalization/ ; Component 9//Romanian Ministry of Research, Innovation and Digitalization/ ; Investment I8//Romanian Ministry of Research, Innovation and Digitalization/ ; },
abstract = {Resting-state functional connectivity (rsFC) is a highly dynamic process that varies across different times of the day within each individual. Although this variability was long considered to be noise, recent evidence suggests it may allow for an optimal adaptation to changes in the environment. However, the way rsFC is shaped on a circadian scale and its association with cognition are still unclear. We analyzed data from 90 late middle-aged participants from the Cognitive Fitness in Aging study (61 women; 50-69 years). Participants completed five electroencephalographic (EEG) recordings of spontaneous resting-state activity spread over 20 h of prolonged wakefulness. Using a temporal multilayer network approach, we characterized the diurnal variations of the dynamic recruitment and integration of resting-state brain networks. We focused on the theta and gamma frequency bands within the default mode network (DMN), central executive network (CEN), and salience network (SN). Additionally, we investigated the relationship between the recruitment and integration of these networks with baseline cognitive performance and at a 7-year longitudinal follow-up, as well as with positron emission tomography (PET) early neuropathological markers of Alzheimer's disease such as β-amyloid and tau/neuroinflammation. Diurnal changes in theta and gamma dynamics were associated with distinct cognitive aspects. Specifically, higher baseline memory performance was associated with higher theta dynamic integration of the SN and the CEN, as well as higher theta dynamic recruitment of the DMN. Moreover, lower longitudinal memory decline at 7 years was associated with higher theta dynamic integration of the SN, CEN, and DMN. In contrast, higher gamma diurnal dynamic integration of the SN and the CEN was associated with lower executive and attentional performance, as well as higher early β-amyloid accumulation, at baseline. These findings suggest that maintaining a balance between network flexibility and stability throughout the diurnal phase of the circadian cycle may play a crucial role in cognitive aging, with stable theta-band connectivity supporting memory, whereas excessive gamma-band stability in the SN and CEN may contribute to executive decline and early amyloid accumulation. These insights highlight the importance of considering time-of-day in brain rsFC studies, calling for a temporal multilayer approach to capture these dynamic patterns more effectively.},
}

@article {pmid41345250,
year = {2025},
author = {Abou-El-Hassan, H and Yahya, T and Zusman, BE and Albastaki, O and Imkamp, HT and Ye, JJ and Percopo, F and Christenson, JR and Al Mansi, MH and Lu, KJ and Gabriely, G and Tatematsu, BK and Habashy, KJ and Lopes, JR and Maghzi, AH and Rezende, RM and Quintana, FJ and Weiner, HL and Izzy, S},
title = {Astrocyte activation persists one year after TBI: a dynamic shift from inflammation to neurodegeneration.},
journal = {Communications biology},
volume = {8},
number = {1},
pages = {1745},
pmid = {41345250},
issn = {2399-3642},
support = {5K08NS123503-03//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; },
mesh = {*Astrocytes/metabolism/pathology ; Animals ; *Brain Injuries, Traumatic/pathology/metabolism/complications ; Mice ; Male ; *Inflammation/pathology ; *Neurodegenerative Diseases/pathology/etiology/metabolism ; Mice, Inbred C57BL ; Disease Models, Animal ; },
abstract = {Traumatic brain injury (TBI) remains a leading cause of chronic neurological impairment, yet the cellular mechanisms underlying long-term neurodegeneration in TBI remain incompletely understood. Astrocytes, the most abundant glial cell type, are central to maintaining neuroglial and neurovascular homeostasis. Following TBI, however, astrocytic activation contributes to sustained inflammation and neurotoxicity. In this study, we employed immunohistochemistry and RNA sequencing to longitudinally profile astrocyte morphology and transcriptional states at acute (2 days), subacute (2 weeks), and chronic (1 year) stages after controlled cortical impact in mice. We identified a temporally evolving astrocyte response-beginning with a pro-inflammatory profile acutely, transitioning through a profile suggestive of mixed inflammatory and neurodegenerative signatures subacutely, and culminating in a chronic state marked generally by expression of Alzheimer's and Parkinson's disease-associated genes. Notably, a subset of astrocyte-derived progenitor cells also was found up to one-year post-injury, expressing markers associated with neurogenesis. These findings reveal that astrocyte activation is not transient but persists chronically, undergoing a dynamic shift from inflammation to degeneration. The observed parallels between astrocyte states in chronic TBI and neurodegenerative disorders underscore their potential role in post-traumatic cognitive decline and highlight astrocyte-targeted interventions as a promising avenue for therapeutic development.},
}

*Astrocytes/metabolism/pathology
Animals
*Brain Injuries, Traumatic/pathology/metabolism/complications
Mice
Male
*Inflammation/pathology
*Neurodegenerative Diseases/pathology/etiology/metabolism
Mice, Inbred C57BL
Disease Models, Animal

@article {pmid41345217,
year = {2025},
author = {Seijo, MA and Banerjee, A and Hernandez, CM},
title = {Network-level organization of systemic inflammation reflects early Alzheimer's-like behavioral changes.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-025-30561-w},
pmid = {41345217},
issn = {2045-2322},
support = {2T32HD071866-06//National Institute of Child Health and Human Development/ ; 1K99AG078400-01/AG/NIA NIH HHS/United States ; },
}

@article {pmid41345047,
year = {2025},
author = {Bahbah, EI},
title = {Tetramethylpyrazine nitrone: a multifaceted neuroprotective agent in neurodegenerative disorders.},
journal = {Neurodegenerative disease management},
volume = {},
number = {},
pages = {1-15},
doi = {10.1080/17582024.2025.2598227},
pmid = {41345047},
issn = {1758-2032},
abstract = {Neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS) share key pathological features, including oxidative stress, mitochondrial dysfunction, and impaired protein homeostasis, yet remain without effective disease-modifying therapies. Tetramethylpyrazine nitrone (TBN), a synthetic derivative of tetramethylpyrazine bearing a free radical-scavenging nitrone moiety, has emerged as a promising multi-target neuroprotective agent. This review synthesizes preclinical and clinical data supporting TBN's therapeutic potential in AD, PD, and ALS. In AD models, TBN reduces amyloid-β accumulation and tau hyperphosphorylation, enhances autophagic clearance, preserves synaptic integrity, and improves cognitive performance. In PD models, TBN confers dopaminergic neuroprotection, restores motor function, and promotes α-synuclein degradation, effects mediated largely through activation of the PGC-1α/Nrf2 pathway and augmentation of the ubiquitin-proteasome system (UPS). In ALS models, TBN mitigates motor neuron loss, improves motor performance, and extends survival, likely via the PGC-1α/Nrf2/HO-1 axis and enhanced autophagic activity. Phase I studies have established TBN's favorable oral and intravenous pharmacokinetics, effective blood - brain barrier penetration, and overall safety and tolerability in healthy volunteers. Owing to its multi-pathway mechanism, principally engaging antioxidant/mitochondrial pathways and proteostasis (autophagy/UPS), TBN represents a compelling candidate for continued clinical development, either as monotherapy or in combination with disease-specific interventions.},
}

@article {pmid41344987,
year = {2025},
author = {Huang, SY and Lin, KJ and Hung, GU and Hsiao, IT},
title = {Updates of nuclear medicine imaging in neurodegenerative disorders.},
journal = {Journal of the Formosan Medical Association = Taiwan yi zhi},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jfma.2025.11.032},
pmid = {41344987},
issn = {0929-6646},
abstract = {Neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), dementia with Lewy bodies (DLB), frontotemporal dementia (FTD), and progressive supranuclear palsy (PSP) are major causes of disability in aging societies. Early and accurate diagnosis is essential but remains challenging due to overlapping clinical presentations and limited sensitivity of conventional tools. Advances in nuclear medicine imaging now enable in vivo visualization of key pathological processes, including amyloid-β and tau deposition, α-synuclein aggregation, dopaminergic dysfunction, neuroinflammation, and altered cerebral metabolism. Recent progress in quantitation frameworks, multimodal integration with fluid biomarkers, and AI-assisted applications is further enhancing reproducibility and clinical translation. In this review, we summarize advances in radiotracer development, clinical applications, and standardization efforts, highlight insights from Taiwan on the integration of molecular imaging into differential diagnostic workflows for dementia and Parkinsonian syndromes, and outline remaining challenges and future directions toward precision medicine in neurodegenerative disorders.},
}

@article {pmid41344886,
year = {2025},
author = {Perovnik, M and Simončič, U and Jamšek, J and Gregorič Kramberger, M and Brumberg, J and Meyer, PT and Perani, D and Caminiti, SP and Brendel, M and Stockbauer, AC and Camacho, V and Alcolea, D and Vandenberghe, R and Van Laere, K and Ko, JH and Lee, CS and Pardini, M and Lombardo, L and Padovani, A and Pilotto, A and Ochoa-Figueroa, MA and Davidsson, A and Cháfer-Pericás, C and Álvarez-Sánchez, L and Garibotto, V and Lemstra, AW and Ferreira, D and Morbelli, SD and Tang, CC and Eidelberg, D and Trošt, M and , },
title = {Metabolic brain networks in dementia with Lewy bodies: from prodromal to manifest disease stages.},
journal = {Journal of neurology, neurosurgery, and psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1136/jnnp-2025-336935},
pmid = {41344886},
issn = {1468-330X},
abstract = {BACKGROUND: Dementia with Lewy bodies (DLB) is the second most common neurodegenerative dementia, yet it remains under-recognised and misdiagnosed, which delays treatment, causes inaccurate prognosis and limits research opportunities. Imaging with 2-[[18]F]fluoro-2-deoxy-D-glucose positron emission tomography (FDG PET) is a supportive DLB biomarker. We evaluated a multivariate, quantifiable metabolic network biomarker, termed DLB-related pattern (DLBRP), for its further clinical translation across centres and disease stages.

METHODS: We analysed demographic, clinical and FDG PET imaging data of 1180 participants from 14 tertiary centres and two multicentre datasets. We included 379 DLB, 28 mild cognitive impairment-LB (MCI-LB), 195 dementia due to Alzheimer's disease (ADD), 172 MCI-AD without α-synuclein co-pathology (MCI-AD-S-), and 73 MCI-AD with α-synuclein co-pathology (S+) patients, along with a comparative group of 333 normal controls (NCs). From the scans, we calculated the expression of DLBRP, AD-related pattern (ADRP) and Parkinson's disease-related pattern (PDRP) and compared them across groups. DLBRP scores were correlated with clinical measurements.

RESULTS: Across independent cohorts, DLBRP robustly distinguished DLB from NCs (sensitivity >89%, specificity >90%), and scores correlated with Unified Parkinson's Disease Rating Scale Part III and independently predicted Mini-Mental State Examination. DLBRP was elevated already in MCI-LB. In a small longitudinal dataset, we observed steady increases in DLBRP expression with scores exceeding the diagnostic threshold prior to dementia onset. DLBRP and PDRP discriminated DLB from ADD (sensitivity, 74%-90%; specificity, 80%). In MCI-AD groups, ADRP was expressed, whereas DLBRP and PDRP were increased only in MCI-AD-S+, although comparatively less than in MCI-LB.

CONCLUSIONS: This study demonstrates the value of DLBRP in diagnosing prodromal and manifest DLB and distinguishing them from their AD counterparts. While overlap between patterns may reflect actual co-pathology, this possibility cannot be accepted without thorough pathological confirmation. The current findings support the use of DLBRP in patient evaluation and in future trial design.},
}

@article {pmid41344825,
year = {2025},
author = {Johnson, SL and Gibbons, SR and Nielsen, CJ},
title = {Theranostics Beyond Oncology: Emerging Applications.},
journal = {Journal of nuclear medicine technology},
volume = {53},
number = {Suppl 1},
pages = {141S-143S},
doi = {10.2967/jnmt.125.271192},
pmid = {41344825},
issn = {1535-5675},
mesh = {Humans ; *Theranostic Nanomedicine/methods ; },
abstract = {Theranostics, the combination of targeted diagnostic imaging and treatment, is rapidly expanding its role beyond oncology into various noncancerous diseases. Recent advances in radiopharmaceuticals, molecular imaging, and nanoparticle-based technologies are enabling the detection and treatment of conditions in cardiology, neurology, autoimmune, and bone marrow disorders. These innovations include targeted imaging and therapy for atherosclerosis and cardiac amyloidosis, as well as neurodegenerative disorders such as Alzheimer disease. Additionally, they encompass biomarkers such as fibroblast activation protein inhibitor and radiolabeled glucocorticoids in autoimmune and inflammatory diseases, as well as the selective ablation of diseased tissue in bone marrow conditioning. Despite the promise of these developments, several challenges must be considered, including the integration of theranostic strategies into standard practice and establishing their efficacy through robust clinical trials. This review examines the emerging nononcologic applications of theranostics, highlighting current research and future potential.},
}

Humans
*Theranostic Nanomedicine/methods

@article {pmid41344577,
year = {2025},
author = {Zhou, R and Lin, X and Liao, Z and Lin, J and Zheng, R and Ni, H and Liu, W and Feng, Z and He, Q and Lin, X and Tang, C and Song, J and Ning, W},
title = {Decoding Senescent Drivers in Alzheimer's Disease: From Bench to Bedside.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {102978},
doi = {10.1016/j.arr.2025.102978},
pmid = {41344577},
issn = {1872-9649},
abstract = {Alzheimer's disease (AD) is the most common neurodegenerative disorder associated with dementia. Cellular senescence, widely acknowledged as a key hallmark of aging, has increasingly been recognized as a significant factor in the pathogenesis of AD, although the precise mechanisms underlying this relationship have yet to be fully understood. In the brains of individuals with AD, neurons, glial cells, and cerebrovascular endothelial cells exhibit premature senescence, characterized by irreversible cell cycle arrest, resistance to apoptosis, and the secretion of a diverse range of bioactive molecules collectively referred to as the senescence-associated secretory phenotype (SASP). These senescent cells profoundly influence the neural microenvironment through the release of SASP factors, thus exacerbating Aβ- and tau-induced neurotoxicity, promoting neuroinflammatory responses, and impairing the integrity of the blood-brain barrier (BBB), ultimately giving rise to a self-sustaining "senescence-neurodegeneration" cycle. Despite progress in therapies targeting Aβ and tau pathology, their clinical effectiveness remains limited, highlighting the urgent need for alternative therapeutic strategies. This review presents a comprehensive analysis of the molecular mechanisms connecting AD with cellular senescence, examines how the senescent microenvironment contributes to neurodegeneration, and evaluates the therapeutic potential of senotherapeutic interventions-including senolytics and senomorphics-as novel approaches for the clinical management of AD.},
}

@article {pmid41344499,
year = {2025},
author = {Pan, JZ and Yu, MY and Tian, MZ and Liu, R and Zhao, W and Luo, Q},
title = {Calcaratarin D exerts neuroprotective effects in Alzheimer's disease mouse model by inhibiting CERT-mediated NF-κB pathway.},
journal = {Experimental neurology},
volume = {},
number = {},
pages = {115585},
doi = {10.1016/j.expneurol.2025.115585},
pmid = {41344499},
issn = {1090-2430},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disease characterized by β-amyloid plaque accumulation, neuroinflammation, and dysregulation of sphingolipid metabolism, mainly manifested as irreversible cognitive decline and memory loss. A key pathological hallmark of AD is neuroinflammation, largely fueled by the persistent stimulation of microglia and subsequent pro-inflammatory cytokine production, which worsens disease development. Calcaratarin D (CalD), a ladanane-type diterpenoid sourced from Hedychium flavum rhizomes, has been reported to exhibit significant anti-inflammatory effects. However, its potential therapeutic benefits in AD remain unknown. Therefore, this research focused on exploring the neuroprotective effects of CalD in AD and elucidating its potential mechanisms. We established a mouse model of AD by targeting delivery of Aβ1-42 oligomers to the hippocampus. Behavioral tests showed that CalD significantly improved the memory loss and spatial learning ability of AD mice. Western blotting and immunofluorescence staining further confirmed that CalD effectively reduced Aβ deposition and inhibited the excessive activation of microglia. Network pharmacology analysis found that the mechanism of action of CalD mainly involved inflammatory signaling pathways and sphingolipid metabolism. Subsequently, in vivo and in vitro experiments confirmed that CalD could inhibit the excessive activation of the TLR4/NF-κB/NLRP3 signaling pathway and restore the ceramide homeostasis in AD mice. On this basis, molecular docking and small interfering RNA experiments further clarified that CalD played an anti-inflammatory and regulatory role in sphingolipid metabolism by targeting CERT. In summary, these findings indicate that CalD exerts neuroprotective effects by modulating neuroinflammation and ceramide metabolic dysregulation, suggesting that CalD has therapeutic potential in AD.},
}

@article {pmid41344495,
year = {2025},
author = {Chen, J and Tian, Y and Wang, L and Zhang, Z and Jin, Q and Xiao, B},
title = {GABAB receptor blockade in the dentate gyrus restores glutamatergic synaptic plasticity and hippocampus dependent memory in an AD-like rat model.},
journal = {Neuropharmacology},
volume = {},
number = {},
pages = {110789},
doi = {10.1016/j.neuropharm.2025.110789},
pmid = {41344495},
issn = {1873-7064},
abstract = {Synaptic dysfunction driven by glutamate-mediated excitotoxicity is a hallmark of hippocampus-dependent memory impairment in Alzheimer's disease (AD). Although GABAergic signaling is known to regulate excitatory/inhibitory (E/I) balance, the precise molecular mechanisms by which GABA and its receptors modulate glutamatergic synaptic plasticity remains incompletely understood. Here, we investigated the role of GABA and its receptors in the dentate gyrus (DG) of a streptozotocin (STZ) induced rat model with sporadic AD (SAD)-like features. sAD rats exhibited intact emotional and motor functions but showed marked impairments in novel object recognition, Y-maze, and Morris water maze (MWM) performance. In vivo microdialysis combined with HPLC during MWM training revealed decreased GABA levels and selective upregulation of GABAB receptor (GABABR) expression, but not GABAAR, expression in the DG. Administration of the GABABR antagonist 2-hydroxysaclofen improved hippocampal memory performance, reduced glutamate accumulation, and restored the key excitatory synaptic markers, including vGlut1 and PSD-95. Moreover, co-immunoprecipitation and molecular docking identified a specific interaction between GABABR and CaMKII. GABABR blockade enhanced CaMKII phosphorylation and activated downstream effectors, including p-CREB and BDNF, indicating re-engagement of plasticity-related signaling. These findings demonstrate that GABABR upregulation in the DG impairs glutamatergic synaptic plasticity and memory function in sAD like rats, likely via direct suppression of the CaMKII/CREB/BDNF pathway. Targeting GABABR may thus offer a promising strategy to restore E/I balance and cognitive performance in a sAD- like rat model.},
}

@article {pmid41344379,
year = {2025},
author = {Brown, CM and Brooks, JK and Kelly, L and Vroom, MM and Longo, M and Dodart, JC and Carare, R and Boyd, JD},
title = {Tau-targeting active immunotherapy slows progression and reduces pathology in mouse models of tauopathy.},
journal = {Brain pathology (Zurich, Switzerland)},
volume = {},
number = {},
pages = {e70056},
doi = {10.1111/bpa.70056},
pmid = {41344379},
issn = {1750-3639},
support = {//Vaxxinity/ ; },
abstract = {A novel class of active immunotherapy, consisting of proprietary T-helper peptide linked to a B-cell epitope, is being developed to target tau in Alzheimer's disease (AD). These experimental therapies generate antibodies that have demonstrated binding to pathological tau in vitro, and efficacy in cell-based tau aggregation assays comparable to monoclonal antibodies. Here, we report the ability of one such tau-targeting immunotherapy, p5555kb, to prevent the progression of tau pathology using two distinct mouse models. P301L mice were immunized with p5555kb and showed greater survival rates at 210 days than saline-inoculated control mice. The efficacy of p5555kb against tau seeding in vivo was assessed by injecting C57BL6 mice with tau fibrils purified from post-mortem human AD brain tissue. Immunization with p5555kb significantly reduced the amount of tau inclusions detected by immunohistochemistry at 9 months post-injection, as compared to saline inoculation. This study demonstrates that p5555kb is effective at inducing functional tau-targeting antibodies, which prevented the onset of adverse phenotypes associated with tau pathology in vitro and in vivo.},
}

@article {pmid41344290,
year = {2025},
author = {Liu, YJ and Wang, XD},
title = {Parallel supramammillary-hippocampal routes: Organization, dysregulation, and restoration.},
journal = {Neuron},
volume = {113},
number = {23},
pages = {3879-3881},
doi = {10.1016/j.neuron.2025.10.020},
pmid = {41344290},
issn = {1097-4199},
mesh = {Animals ; *Hippocampus/physiology ; Alzheimer Disease/physiopathology/pathology ; Neural Pathways/physiology ; Mice ; Humans ; },
abstract = {In this issue of Neuron, Luo et al.[1] report two supramammillary neuronal populations with segregated projections to the dorsal and ventral dentate gyrus that selectively modulate cognitive and emotional processes, respectively. Targeted activation of each pathway alleviates domain-specific behavioral deficits in an Alzheimer's disease mouse model.},
}

Animals
*Hippocampus/physiology
Alzheimer Disease/physiopathology/pathology
Neural Pathways/physiology
Mice
Humans

@article {pmid41344273,
year = {2025},
author = {Wang, Q and Wang, W and Zhu, H and Huang, Y and Huang, R and Yang, Y and Liao, Y},
title = {Mechanisms of naozhenning in inhibiting neuronal ferroptosis and alleviating brain recurrent mild traumatic brain injury in a rat model.},
journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology},
volume = {150},
number = {},
pages = {157637},
doi = {10.1016/j.phymed.2025.157637},
pmid = {41344273},
issn = {1618-095X},
abstract = {BACKGROUND: Recurrent mild traumatic brain injury (rmTBI) represent a significant predisposing factor for the development of neurodegenerative diseases, including but not limited to Parkinson's disease and Alzheimer's disease. However, its underlying pathological mechanisms remain unclear, and there are currently no definitive clinical treatments available. Naozhenning, an empirical formula used to treat brain concussions, comprises multiple medicinal components and exhibits a potential for treating rmTBI. Nonetheless, its material basis and efficacy for rmTBI alleviation are still unknown.

PURPOSE: This research aims to determine the role of ferroptosis in hippocampal neurons following rmTBI and to elucidate Naozhenning's neuroprotective mechanisms towards rmTBI.

METHODS: A mild cerebral concussion (MCC) rat model was established using a free-fall injury method. To evaluate the extent and temporal progression of hippocampal ferroptosis, different impact heights and various post-injury time points (48 h, 7, 14, and 21 days) were tested. The changes associated with ferroptosis were assessed using Prussian blue staining, transmission electron microscopy (TEM), and Western blotting. Upon identification of the peak period of neuronal ferroptosis, Naozhenning was introduced to assess its regulatory effects. Subsequently, a comprehensive "drug-component-target-pathway" network was systematically constructed by integrating high-resolution liquid chromatography-mass spectrometry, network pharmacology, and molecular docking. The core active components and key molecular targets predicted by this network were then experimentally validated through in vitro assays.

RESULTS: Hippocampal neuronal ferroptosis in MCC model was positively associated with both injury severity and duration. Naozhenning significantly alleviated neuronal injury and improved learning and spatial memory in rats, exerting its effect primarily through the suppression of hippocampal ferroptosis. Integrated chromatographic and computational analyses revealed that quercetin and lutein as key bioactive constituents in Naozhenning. Molecular docking and cellular assays confirmed that these compounds inhibit ferroptosis by modulating the HMOX1 protein.

CONCLUSION: Our findings demonstrate that ferroptosis underlies rmTBI pathogenesis, and that Naozhenning confers neuroprotection by mitigating hippocampal neuronal injury and improving cognitive function in MCC rats, primarily through the inhibition of ferroptosis via the actions of quercetin and luteolin on HMOX1.},
}

@article {pmid41344159,
year = {2025},
author = {Zhang, J and Luo, Y and Xie, C and Zhang, M and Qin, H and Zhou, Y and Wu, X and Hu, C and Hu, F and Fei, X and Zhang, H and Li, J and Fu, Y and Yuan, Y and Yang, S and Gao, D},
title = {PHGDH-dependent serine metabolism in astrocytes: A key regulator of oxidative stress and pyroptosis in cerebral ischemia-reperfusion injury.},
journal = {Redox biology},
volume = {89},
number = {},
pages = {103954},
doi = {10.1016/j.redox.2025.103954},
pmid = {41344159},
issn = {2213-2317},
abstract = {Phosphoglycerate dehydrogenase (PHGDH) is a key molecule in the progression of Alzheimer's disease. Herein, we report that PHGDH exerts a significant influence on cerebral ischemia-reperfusion injury (CIRI). Ischemia-reperfusion injury is predominantly triggered by oxidative stress and inflammatory responses; however, the underlying molecular mechanisms remain incompletely understood. Our findings demonstrate that PHGDH displays predominant expression in brain astrocytes and undergoes time-dependent alterations in reactive astrocytes following cerebral ischemia-reperfusion. Specifically, targeted knockdown of PHGDH expression in astrocytes substantially exacerbates pathological damage and neurological deficits post cerebral ischemia-reperfusion. Subsequent mechanistic analyses unveiled that PHGDH knockdown predominantly facilitates astrocyte pyroptosis and neuroinflammation. Specifically, downregulation of PHGDH in astrocytes induces oxidative stress, augments ROS production, and diminishes antioxidant levels of GSH and NADPH. Moreover, PHGDH downregulation disrupts the mitochondrial respiratory chain, triggering mitochondrial damage and dsDNA release during ischemia-reperfusion, thereby exacerbating oxidative stress. Collectively, these mechanisms culminate in AIM2 inflammasome activation, as evidenced by substantial increases in AIM2, ASC, and Cleaved Caspase-1 expression. Notably, exogenous depletion of serine and glycine fails to fully explain the astrocyte pyroptosis triggered by PHGDH knockdown. In conclusion, downregulation of PHGDH in astrocytes post cerebral ischemia-reperfusion predominantly drives astrocyte pyroptosis via oxidative stress, resulting in the release of pro-inflammatory cytokines (e.g., IL-1β and IL-18) and subsequent exacerbation of ischemia-reperfusion injury. These novel insights into the role of PHGDH may inform the development of targeted therapeutic strategies for cerebral ischemia-reperfusion.},
}

@article {pmid41344108,
year = {2025},
author = {Dong, A and Cao, J and Sarrigiannis, PG and Blackburn, D and Starr, A and Zhao, Y},
title = {A Causal Validation augmented Temporal Convolutional Framework for Brain Effective Connectivity Networks Estimation.},
journal = {Neural networks : the official journal of the International Neural Network Society},
volume = {196},
number = {},
pages = {108405},
doi = {10.1016/j.neunet.2025.108405},
pmid = {41344108},
issn = {1879-2782},
abstract = {Advancements in neuroimaging have facilitated unprecedented insights into brain connectivity, making the study of brain effective connectivity networks (ECNs) essential for understanding neurological functions and diseases. Recently, neural networks (NNs) have emerged as powerful tools for ECN estimation due to their prominent universal approximation ability and less reliance on prior knowledge. However, most NN-based approaches fail to eliminate redundant temporal information and lack rigorous causal validation mechanisms. This paper introduces a novel end-to-end framework for estimating ECNs utilising Least Absolute Shrinkage and Selection Operator (Lasso) regression of Temporal Convolutional Networks (TCNs), named the Causal Validation augmented Temporal Convolutional Framework (CVTCF). In the CVTCF, a convolutional Hierarchical Group Lasso (cHGL) is proposed to detect Granger Causality (GC) inputs and eliminate redundant temporal information during GC detection. Additionally, the framework incorporates permutation importance validation based on the Wilcoxon signed-rank test to enhance the reliability of GC detection. The proposed CVTCF generally outperformed state-of-the-art methods in a controlled simulation using the chaotic Lorenz-96 model and the publicly available blood-oxygen-level-dependent (BOLD) benchmark dataset. Furthermore, the proposed CVTCF has enabled a detailed analysis of the causal interactions within the cerebral cortex, bringing to light the intricate relationships that underlie neurological functioning and impairment of neurodegenerative conditions like Alzheimer's Disease (AD) and Parkinson's Disease (PD). This study demonstrates the potential of using ECN estimation based on the CVTCF as indicators for neurodegenerative diseases and paves the way for future diagnostic and therapeutic strategies.},
}

@article {pmid41344072,
year = {2025},
author = {Kaewta, C and Pitakaso, R and Khonjun, S and Srichok, T and Luesak, P and Gonwirat, S and Enkvetchakul, P and Matitopanum, S and Srisuwandee, T},
title = {QENNA: A quantum-enhanced neural network for early Alzheimer's detection using magnetic resonance imaging.},
journal = {Artificial intelligence in medicine},
volume = {172},
number = {},
pages = {103322},
doi = {10.1016/j.artmed.2025.103322},
pmid = {41344072},
issn = {1873-2860},
abstract = {Early detection of Alzheimer's disease (AD) is essential for effective clinical intervention and disease management. However, conventional Deep Learning (DL) methods face limitations in analyzing complex brain magnetic resonance imaging (MRI), especially when training data are scarce. In this study, we propose a Quantum-Enhanced Neural Network Architecture (QENNA) that integrates quantum convolutional layers with classical deep learning to improve diagnostic accuracy in early AD detection. The model also incorporates quantum data augmentation strategies, including Quantum Generative Adversarial Networks (QGANs) and quantum random walks, to generate high-fidelity synthetic MRI scans and address training data limitations. Experiments on two public MRI datasets demonstrate that QENNA achieves up to 93.0 % accuracy and 96.0 % Area Under the Curve (AUC), outperforming state-of-the-art classical models. Ablation studies confirm that the quantum components substantially enhance performance. These results suggest that quantum-enhanced learning frameworks can significantly advance Artificial Intelligence (AI)-driven diagnostic tools for neurodegenerative disorders and support scalable, early-stage AD screening in clinical practice.},
}

@article {pmid41343876,
year = {2025},
author = {Zhang, F and Chen, L and Jin, J and Ma, H and Li, Y and Xiao, T and Zeng, Y and Yang, J and Hao, X and Yuan, C},
title = {Anti-neuroinflammatory polyprenylated acylphloroglucinols from Hypericum patulum: LC-MS/MS-guided isolation, semi-synthesis, and TLR4 inhibition.},
journal = {Bioorganic chemistry},
volume = {168},
number = {},
pages = {109292},
doi = {10.1016/j.bioorg.2025.109292},
pmid = {41343876},
issn = {1090-2120},
abstract = {Alzheimer's disease (AD) is a serious disease that poses a major threat to human health. Up till now, there is no effective drug on the market that could completely cure AD. In this study, 45 polycyclic polyprenylated acylphloroglucinol (PPAP) analogs, including 13 new ones, were isolated from Hypericum patulum by LC-MS/MS guided isolation with molecular networking analysis. Architecturally, all isolates consist of 12 cage-like PPAPs, 24 type-A PPAPs, four seco-PPAPs, three spiroType PPAPs, and two adamantane-type PPAPs. Semi-synthesis was applied for the first time to assign the relative and absolute configuration of those PPAPs (1-8) with an oxidized prenyl group. Those compounds were identified by various spectral data, quantum chemical calculations, and single crystal X-ray diffraction. Fourteen compounds exhibited better NO inhibitory effect with IC50 values of 1.97 ± 0.44-13.97 ± 1.45 μM than that of the positive control, minocycline (IC50: 14.09 ± 1.14) in BV-2 cells. The structure activity relationship was also discussed. Further mechanistic study for a high content compound (4) implied that this compound could suppress the expression of TLR4, prohibit TLR4/NF-κB/JNK signaling pathway, and reduce iNOS and COX-2 expression. Compound 4 could directly bind to TLR4 via cellular thermal shift assay (CETSA), surface plasmon resonance assay (SPR), and molecular docking. What's more, compound 4 exhibited remarkable anti-AD effects without toxicity in zebrafish model. Thus, compound 4 is a potential anti-AD lead compound by targeting TLR4.},
}

@article {pmid41343844,
year = {2025},
author = {Pai, MC and Lin, YT and Hsiao, CY and Lai, CH and Chen, CJ and Hu, CJ and Chen, CY},
title = {Using Virtual Reality to Assess Spatial Navigation Ability in Individuals With Mild Cognitive Impairment and Older Adults: Cross-Sectional Study.},
journal = {JMIR aging},
volume = {8},
number = {},
pages = {e75952},
doi = {10.2196/75952},
pmid = {41343844},
issn = {2561-7605},
mesh = {Humans ; *Cognitive Dysfunction/diagnosis/psychology/physiopathology ; *Virtual Reality ; Male ; Female ; Aged ; *Spatial Navigation/physiology ; Cross-Sectional Studies ; Aged, 80 and over ; Middle Aged ; Feasibility Studies ; },
abstract = {BACKGROUND: Spatial navigation impairment is prevalent in people with Alzheimer disease (AD) and may appear in its initial clinical stage. Detecting this deficit in people at risk may not only help prevent them from getting lost or going missing but also provide a useful clinical aid to accurate diagnosis. Traditional assessments for spatial navigation impairment include questionnaires, paper-and-pencil and maze tests, or video games. While a real-world setting is more valid, direct, and accurate, it is plagued by unpredictable conditions such as weather, obstacles, or accidents. Owing to modern technology, virtual reality (VR) offers a new way to test spatial navigation impairment.

OBJECTIVE: The aims of this study were to test the feasibility of a VR setting to assess sense of location in people with mild cognitive impairment (MCI) and the power of VR to discriminate among groups with different clinical conditions.

METHODS: We used the Pai-Jan virtual reality (PJVR) device to test spatial navigation ability in those who were cognitively unimpaired (CU) and those who experienced subjective cognitive decline (SCD) and MCI. The PJVR device is the VR version (VIVE Pro Eye head-mounted display) of the Pai-Jan device, which has demonstrated its power to discriminate among CU, AD MCI, and mild AD dementia. With a map provided and using joysticks or handles, participants were asked to reach 5 points on a 660-m path. Linear deviation (LD; in meters) from each target point and vector deviation (in degrees) from the direction to the start point at each location were treated as the variables for comparison.

RESULTS: A total of 113 participants provided informed consent to initiate the study. Of these 113 participants, 93 (82.3%) completed the trials, including 22 (24%) who were CU, 39 (42%) with SCD, and 32 (34%) with MCI. In total, 17.7% (20/113) failed the trials due to cybersickness. The mean LD of the CU, SCD, and MCI groups was 38.2 (SD 39.5), 50.4 (SD 40.7), and 100.4 (SD 46.2) meters, respectively (P<.001). The MCI group showed greater vector deviation (mean 63.2, SD 42.4 degrees) than either the SCD (mean 39.4, SD 33.0 degrees) or CU (mean 38.6, SD 37.4 degrees; P=.02) group. The LD of the PJVR device was correlated with the total scores on the caregiver version of the Questionnaire on Everyday Navigational Ability (P<.001), indicating good ecological validity.

CONCLUSIONS: The PJVR device is feasible for older adults and participants with MCI. It can detect spatial navigation deficits related to AD pathology, and the results show a close correlation with real-world navigation ability.},
}

Humans
*Cognitive Dysfunction/diagnosis/psychology/physiopathology
*Virtual Reality
Male
Female
Aged
*Spatial Navigation/physiology
Cross-Sectional Studies
Aged, 80 and over
Middle Aged
Feasibility Studies

@article {pmid41346453,
year = {2024},
author = {Li, C and Sheng, Z and Cohen, T and Pakhomov, S},
title = {Too Big to Fail: Larger Language Models are Disproportionately Resilient to Induction of Dementia-Related Linguistic Anomalies.},
journal = {Findings of ACL. ACL},
volume = {2024},
number = {},
pages = {6363-6377},
pmid = {41346453},
abstract = {As artificial neural networks grow in complexity, understanding their inner workings becomes increasingly challenging, which is particularly important in healthcare applications. The intrinsic evaluation metrics of autoregressive neural language models (NLMs), perplexity (PPL), can reflect how "surprised" an NLM model is at novel input. PPL has been widely used to understand the behavior of NLMs. Previous findings show that changes in PPL when masking attention layers in pre-trained transformer-based NLMs reflect linguistic anomalies associated with Alzheimer's disease dementia. Building upon this, we explore a novel bidirectional attention head ablation method that exhibits properties attributed to the concepts of cognitive and brain reserve in human brain studies, which postulate that people with more neurons in the brain and more efficient processing are more resilient to neurodegeneration. Our results show that larger GPT-2 models require a disproportionately larger share of attention heads to be masked/ablated to display degradation of similar magnitude to masking in smaller models. These results suggest that the attention mechanism in transformer models may present an analogue to the notions of cognitive and brain reserve and could potentially be used to model certain aspects of the progression of neurodegenerative disorders and aging.},
}

@article {pmid41343567,
year = {2025},
author = {He, Y and Yan, Z and Liang, Y and Yu, Y},
title = {Abnormal brain network reconfiguration in neuropsychiatric disorders across cognitive decline, Depression, and Schizophrenia.},
journal = {PloS one},
volume = {20},
number = {12},
pages = {e0337470},
doi = {10.1371/journal.pone.0337470},
pmid = {41343567},
issn = {1932-6203},
mesh = {Humans ; *Schizophrenia/physiopathology ; *Cognitive Dysfunction/physiopathology ; Male ; Female ; Aged ; *Brain/physiopathology ; *Depressive Disorder, Major/physiopathology ; Electroencephalography ; Middle Aged ; Alzheimer Disease/physiopathology ; *Nerve Net/physiopathology ; Machine Learning ; Case-Control Studies ; },
abstract = {OBJECTIVE: Neuropsychiatric disorders are characterized by high complexity and comorbidity, imposing a substantial burden on both patients and society. However, their elusive pathogenic mechanisms impede accurate clinical diagnosis and effective interventions. To overcome this challenge, the present study proposes a novel framework to quantify and characterize these disorders.

METHODS: Routine electroencephalogram (EEG) recordings are acquired from 236 subjects, including patients with Alzheimer's disease (AD), mild cognitive impairment (MCI), major depressive disorder (MDD), schizophrenia, and healthy controls (HCs). Time-varying functional brain networks are constructed by phase locking value (PLV) analysis on band-pass filtered EEG signals. Subsequently, the nodal behavior characteristics within these dynamic brain networks are quantified by integrating robust dynamic community detection algorithms and network reconfiguration metrics.

RESULTS: Significant intergroup differences in network reconfiguration metrics are identified based on the dynamic community structures (FDR-corrected p < 0.001). Lower cohesion strength is observed across all neuropsychiatric disorders compared to healthy controls, consistent across all frequency bands and recording sites. When six machine learning classifiers are trained on these metrics, the maximum classification accuracies exceeded 80%. Since lower cohesion strength is a prominent potential biomarker for neuropsychiatric disorders, it was then selected as the independent input feature for random forest classifier, and the classification accuracy achieved 0.85 for schizophrenia group, 0.88 for both the MCI and MDD group, and 0.82 for the AD group.

CONCLUSIONS: Our findings indicate that the framework based on dynamic network reconfiguration metrics effectively captures both the shared and disorder-specific alterations in brain network dynamics among neuropsychiatric disorders.

SIGNIFICANCE: Dynamic community structure advances our understanding of the pathological mechanisms underlying neuropsychiatric disorders. This study provides novel insights that may inform the development of more targeted and effective therapeutic strategies.},
}

Humans
*Schizophrenia/physiopathology
*Cognitive Dysfunction/physiopathology
Male
Female
Aged
*Brain/physiopathology
*Depressive Disorder, Major/physiopathology
Electroencephalography
Middle Aged
Alzheimer Disease/physiopathology
*Nerve Net/physiopathology
Machine Learning
Case-Control Studies

@article {pmid41343337,
year = {2025},
author = {Dong, H and Chen, W and Lv, X and Jiang, Y and Cheng, M and Chang, A and Zhou, Y and Wang, T and Zhang, Y and Li, Z and Zhou, Y and Xu, M},
title = {A Turn-On Fluorescent and Ratiometric Electrochemical Dual-Mode Probe for Hydrogen Peroxide Detection in Brain Microdialysates of Alzheimer's Disease Mice.},
journal = {Analytical chemistry},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.analchem.5c05358},
pmid = {41343337},
issn = {1520-6882},
abstract = {Hydrogen peroxide (H2O2), a pivotal reactive oxygen species (ROS), is closely linked to oxidative stress in the pathogenesis of Alzheimer's disease (AD). Herein, we report a dual-mode probe (Re-PS) integrating turn-on fluorescence and ratiometric electrochemistry for the selective detection of H2O2 in brain microdialysates of AD model mice. The probe is constructed using resorufin (Re) as a dual-signal reporter and a pentafluorobenzenesulfonyl (PS) group as the H2O2-responsive unit. Upon reaction with H2O2, the PS group undergoes nucleophilic substitution, leading to the release of Re; this process triggers a fluorescence "turn-on" response and generates a ratiometric electrochemical signal. Compared with ester-based probes, Re-PS shows superior stability due to the strong electron-withdrawing effect of fluorine atoms in the PS group. The fluorescence mode achieves a detection limit (LOD) of 50 nM, while the electrochemical detection mode (using a carbon fiber microelectrode modified with carbon nanotubes (CFME/CNT)) has a detection range of 1.0-50 μM. Both modes exhibit excellent selectivity against other ROS and biomolecules. In vivo microdialysis analysis reveals significantly elevated H2O2 levels in the brains of AD mice (28.6 ± 3.2 μM) compared with wild-type mice (10.3 ± 1.8 μM). This dual-mode strategy enables cross-validation, providing a reliable tool for monitoring oxidative stress in neurodegenerative diseases.},
}

@article {pmid41343238,
year = {2025},
author = {Chérot, H and Pred'homme, T and Thai, R and Théodoro, F and Castelli, F and Theillet, FX},
title = {In-Cell Residue-Resolved NMR of Micromolar α-Synuclein and Tau at 310 K.},
journal = {Journal of the American Chemical Society},
volume = {},
number = {},
pages = {},
doi = {10.1021/jacs.5c15061},
pmid = {41343238},
issn = {1520-5126},
abstract = {Aggregates of nonglobular proteins are associated with several degenerative disorders, e.g., α-synuclein and tau involved in Parkinson's and Alzheimer's diseases. Do these proteins undergo progressive changes in their conformations and interactions in pathologic situations? In-cell NMR provides atomic-scale information in live cells but, until now, only at ∼283 K in the case of unfolded proteins. Here, we report new labeling and acquisition methods enabling in-cell NMR at 310 K to study these proteins at micromolar concentrations, i.e., native cellular abundances. We used stable human cell lines expressing α-synuclein or tau upon induction in a culture medium supplemented with [13]C-labeled amino acids, or precursors thereof. Acquiring [13]Cα-[13]CO spectra permitted an early residue-resolved analysis of α-synuclein and tau at 310 K and <10 μM in HEK cells at 700 MHz. We detected disordered conformations and patterns of extended cellular interactions for α-synuclein wild-type and two mutants (F4A, A30P), which suggests the appearance of a subpopulation binding to lipid membrane at 310 K. Only the disordered N-terminus of tau was observable, even upon microtubule dismantling by colchicine. This shows that supplementary binding partners interfere with tau in cells. Our approach offers an excellent scalability, in signal, and resolution, up to 1.2 GHz. [13]C-labeling and [13]C-detected NMR spectroscopy in live human cells are thus viable techniques for in-cell structural biology.},
}

@article {pmid41343129,
year = {2025},
author = {Chen, Y and Kong, W and Liu, K and Wei, K and Wen, G and Yu, Y and Zhu, Y},
title = {An Improved Deep Semi-supervised JNMF Method for Biomarker Extraction of Alzheimer's Disease.},
journal = {Journal of molecular neuroscience : MN},
volume = {75},
number = {4},
pages = {159},
pmid = {41343129},
issn = {1559-1166},
support = {No.18ZR1417200//Natural Science Foundation of Shanghai Municipality/ ; },
mesh = {*Alzheimer Disease/diagnostic imaging/genetics/diagnosis ; Humans ; Biomarkers ; Polymorphism, Single Nucleotide ; Algorithms ; Brain/diagnostic imaging/metabolism ; Male ; Female ; },
abstract = {Imaging genetics is an approach that explores the underlying mechanisms of brain disorders such as Alzheimer's disease (AD) by analyzing the correlation between neuroimaging and genetic data. Traditional non-negative matrix factorization (NMF) algorithms are based on linear assumptions, which limits the potential of nonlinear feature extraction among multi-omics data. This study proposes a novel joint-connectivity-based deep semi-supervised non-negative matrix factorization (JCB-DSNMF) model to overcome this limitation and incorporate prior knowledge from both within and between different modalities of data. The model effectively integrates physiological constraints such as connectivity to identify regions of interest (ROI), risk genes, and risk SNP loci associated with AD patients. JCB-DSNMF outperformed other NMF-based algorithms, such as JDSNMF and NMF, in identifying and predicting biologically relevant biomarkers closely related to AD from essential modules. The accuracy of the selected features was further validated by constructing a diagnostic model with high classification accuracy, achieving an AUC value of 0.8621 on the test set. In particular, the brain region Putamen_L and the gene RALGAPB achieved AUC values of 0.903 and 0.924, respectively, highlighting the importance of these features in early AD diagnosis.},
}

*Alzheimer Disease/diagnostic imaging/genetics/diagnosis
Humans
Biomarkers
Polymorphism, Single Nucleotide
Algorithms
Brain/diagnostic imaging/metabolism
Male
Female

@article {pmid41343056,
year = {2025},
author = {Irwin, DJ},
title = {Where do PDD and DLB SYNdromes fit in neuronal alpha-SYNuclein biological frameworks?.},
journal = {Journal of neural transmission (Vienna, Austria : 1996)},
volume = {},
number = {},
pages = {},
pmid = {41343056},
issn = {1435-1463},
support = {National Institute on Aging/AG/NIA NIH HHS/United States ; },
abstract = {Lewy body disorders (LBD) are a spectrum of neurodegenerative diseases characterized by the presence of misfolded neuronal alpha-synuclein (aSYN) pathology in the central and peripheral nervous system. LBDs have heterogeneous clinical presentations, which include dementia with Lewy bodies (DLB), Parkinson's disease (PD), and PD with dementia (PDD). Thus, LBD clinical syndromes (PD/PD/DLB) represent clinicopathologic entities (i.e. constellations of symptoms and supportive biomarkers with a high specificity for underlying aSYN pathology), but clinical features between PDD and DLB largely overlap. Indeed, there is longstanding debate over the utility of the clinical designation between PDD and DLB due to shared underlying pathology, genetic risk factors and prodromal features. Recent advances in the ability to detect pathological aSYN from peripheral fluids/tissues in living patients has ushered in a new era of biological classification of LBD, providing opportunity to improve antemortem diagnosis and facilitate disease-modifying therapeutic trials. The clinical interpretation of these and future aSYN-specific biological tests will be complex, and the reconciliation of classic LBD syndromes with emerging biological classification schemes for LBD and other neurodegenerative disorders is a priority. Indeed, varying burden of aSYN is also found postmortem in > 50% of clinical Alzheimer's disease (AD), and to a lesser frequency as co-pathology in other neurodegenerative disorders, and incidentally in adults without neurologic disease. This review summarizes autopsy-confirmed data on the clinical expression of LBDs and the boundaries between PDD, DLB and mixed-pathology AD to inform the interpretation of emerging biological tests for aSYN and biological classification schemes for LBD and AD.},
}

@article {pmid41343028,
year = {2025},
author = {Patil, V and Sharma, A and Parekh, B and Farah, H and Jyothi, SR and Mishra, S and Nanda, A and Al-Hasnaawei, S and Mishra, MK},
title = {Targeting Microglial Activation to Modulate Neuroinflammation in Alzheimer's Disease.},
journal = {Neuromolecular medicine},
volume = {27},
number = {1},
pages = {76},
pmid = {41343028},
issn = {1559-1174},
mesh = {*Alzheimer Disease/drug therapy/immunology/pathology ; *Microglia/physiology/drug effects/immunology ; Humans ; *Neuroinflammatory Diseases/drug therapy ; Animals ; Signal Transduction/drug effects ; Receptors, Immunologic/antagonists & inhibitors/physiology ; *Molecular Targeted Therapy ; Membrane Glycoproteins/physiology/antagonists & inhibitors ; Neuroprotective Agents/therapeutic use/pharmacology ; Plaque, Amyloid ; Amyloid beta-Peptides ; },
abstract = {Alzheimer's disease is a multifaceted neurodegenerative condition marked by the build-up of amyloid plaques and neurofibrillary tangles that lead to progressive cognitive impairment. Neuroinflammation, especially the activation of microglia, plays a pivotal part in driving this pathology. Microglia are the brain's resident immune cells and can adopt a spectrum of activation states that support either neuroprotection or neurodegeneration. Evidence shows that their phenotypes are highly dynamic and shaped by environmental influences and pathological signals. During the early phases of the disease, microglia tend to assume anti-inflammatory roles that facilitate plaque clearance and promote tissue recovery. Prolonged or dysregulated activation, however, shifts them toward a pro-inflammatory state that amplifies neuronal damage. Several molecular pathways including JAK STAT, PI3K AKT, and MAPK are central to regulating these processes and have emerged as promising therapeutic targets. This review summarizes current insights into microglial phenotypic transitions, the signaling mechanisms governing their activation, and the therapeutic potential of modulating neuroinflammation. Enhancing the neuroprotective capacity of microglia, suppressing chronic inflammatory responses, and targeting key receptors such as TREM2 and P2 × 7 represent potential strategies. A deeper understanding of microglial interactions with other glial cells and the molecular drivers of their activation may provide new avenues for slowing or halting the progression of Alzheimer's disease and related neurodegenerative disorders.},
}

*Alzheimer Disease/drug therapy/immunology/pathology
*Microglia/physiology/drug effects/immunology
Humans
*Neuroinflammatory Diseases/drug therapy
Animals
Signal Transduction/drug effects
Receptors, Immunologic/antagonists & inhibitors/physiology
*Molecular Targeted Therapy
Membrane Glycoproteins/physiology/antagonists & inhibitors
Neuroprotective Agents/therapeutic use/pharmacology
Plaque, Amyloid
Amyloid beta-Peptides

@article {pmid41342958,
year = {2025},
author = {Li, X and Liu, Y and Hu, H and Li, S},
title = {Targeting Liquid-Liquid Phase Separation and Autophagy in Alzheimer's Disease: Insights into Molecular Mechanisms and Therapeutic Potential.},
journal = {Neurochemical research},
volume = {51},
number = {1},
pages = {9},
pmid = {41342958},
issn = {1573-6903},
support = {U24A20806//National Natural Science Foundation of China/ ; 82404605//National Natural Science Foundation of China/ ; U23A20510//National Natural Science Foundation of China/ ; BX20220048//National Postdoctoral Program For Innovative Talents/ ; 2022MD723713//China Postdoctoral Science Foundation/ ; },
mesh = {*Alzheimer Disease/metabolism/drug therapy/pathology ; Humans ; *Autophagy/physiology/drug effects ; Animals ; Amyloid beta-Peptides/metabolism ; tau Proteins/metabolism ; Phase Separation ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the leading cause of dementia, marked by cognitive decline and memory loss. Its multifactorial etiology involves genetic, environmental, and cellular factors, with key pathological features including amyloid-beta (Aβ) plaques and tau tangles. Recent studies have highlighted the roles of liquid-liquid phase separation (LLPS) and autophagy in AD onset and progression. LLPS, an emerging biophysical phenomenon, facilitates protein aggregation and may contribute to early disease stages. Dysregulated autophagy results in the accumulation of toxic proteins, such as Aβ and tau, exacerbating neurodegeneration. This review explores the interplay between LLPS and autophagy in AD, a relationship often overlooked in the literature. It examines their biological mechanisms, synergistic effects on AD pathology, and potential therapeutic strategies. Additionally, we discuss the therapeutic potential of both natural and non-natural compounds in modulating LLPS and autophagy. While compounds like curcumin show promise, a comprehensive framework for their targeted use remains under development. This review provides theoretical support for the advancement of more precise AD therapies.},
}

*Alzheimer Disease/metabolism/drug therapy/pathology
Humans
*Autophagy/physiology/drug effects
Animals
Amyloid beta-Peptides/metabolism
tau Proteins/metabolism
Phase Separation

@article {pmid41342775,
year = {2025},
author = {Jangra, J and Gajanan Bajad, N and Kumar, A and Singh, SK},
title = {Integrated pharmacophore-based virtual screening and molecular modeling approaches for the identification of sigma-2 receptor antagonists as novel therapeutics against Alzheimer's disease.},
journal = {Journal of biomolecular structure & dynamics},
volume = {43},
number = {17},
pages = {10281-10305},
doi = {10.1080/07391102.2024.2446666},
pmid = {41342775},
issn = {1538-0254},
mesh = {*Alzheimer Disease/drug therapy/metabolism ; *Receptors, sigma/antagonists & inhibitors/chemistry/metabolism ; Molecular Docking Simulation ; Humans ; Ligands ; Molecular Dynamics Simulation ; Protein Binding ; *Models, Molecular ; Drug Discovery ; Blood-Brain Barrier/metabolism ; Pharmacophore ; },
abstract = {Alzheimer's disease (AD) is a progressive and irreversible neurodegenerative disorder with a conundrum pathophysiology. Disruption of cholesterol homeostasis in AD is well known. Recently, sigma-2 ligands have been reported for their involvement in abnormal lipid metabolism associated with AD that may lead to disturbance in amyloid-β (Aβ) production, over activity of β- and γ- secretase enzymes, and neuroinflammation. Therefore, targeting sigma-2 receptor inhibition is a plausible mechanism to combat AD. Computational tools aid in screening substantial chemical libraries to unveil potential leads against the desired protein target in less time and cost-effectively. In the present study, five chemical databases (Molport, Mcule, Zinc, ChEMBL, and Enamine) were screened against a pharmacophore model, followed by removing duplicates. The obtained 12,811 hits were subjected to PAINS (Pan assay interference compounds), BRENK (Brenk's rule-based filters), Lipinski's rule of five, structural diversity, and BBB (blood-brain barrier) permeability filters followed by comprehensive molecular docking studies. Further, the top fifteen hits obtained were evaluated based on their predicted pharmacokinetic and toxicity profiles. The binding free energy (ΔG) calculations were carried out for the selected hits by performing an MMPBSA (Molecular mechanics Poisson-Boltzmann surface area) assay followed by regressive MD simulation studies. Finally, ZINC00184959872, ZINC001704299697, and MolPort-046-745-161 were obtained as potential virtual leads against the specific sigma-2 receptor with ΔG values of -34.09, -30.93 and -28.03 kcal/mol, respectively, satisfying all the significant parameters undertaken for the study along with optimum pharmacokinetic properties, minimal toxicity, acceptable RMSD value, and stable protein-ligand complex trajectory throughout the MD simulation run (200 ns).},
}

*Alzheimer Disease/drug therapy/metabolism
*Receptors, sigma/antagonists & inhibitors/chemistry/metabolism
Molecular Docking Simulation
Humans
Ligands
Molecular Dynamics Simulation
Protein Binding
*Models, Molecular
Drug Discovery
Blood-Brain Barrier/metabolism
Pharmacophore

@article {pmid41342719,
year = {2026},
author = {Su, H and Liu, Z and Wei, J and Liu, Y and Zhong, Y and Liu, X and Tan, C and Chen, L},
title = {PDK4 suppresses high glucose-induced microglial ferroptosis by restricting pro-ferroptotic PUFA biosynthesis.},
journal = {Neuroreport},
volume = {37},
number = {1},
pages = {1-10},
doi = {10.1097/WNR.0000000000002234},
pmid = {41342719},
issn = {1473-558X},
mesh = {*Ferroptosis/drug effects/physiology ; Animals ; *Glucose/pharmacology ; Mice ; *Microglia/metabolism/drug effects ; Oxidative Stress/drug effects/physiology ; *Fatty Acids, Unsaturated/biosynthesis/metabolism ; *Pyruvate Dehydrogenase Acetyl-Transferring Kinase/metabolism ; Lipid Peroxidation/drug effects ; Reactive Oxygen Species/metabolism ; Mitochondria/metabolism/drug effects ; },
abstract = {BACKGROUND: Diabetes significantly elevates the risk of neurodegenerative disorders, including Alzheimer's disease and Parkinson's disease, indicating shared pathophysiological mechanisms. While ferroptosis is increasingly implicated in neurodegeneration, microglia - highly vulnerable to ferroptosis - may mediate this link. However, it remains unknown whether high glucose (HG) directly induces microglial ferroptosis.

METHODS: Using HG-treated BV2 microglia, we integrated multiomics profiling (RNA-seq and targeted lipidomics), functional assays, and genetic manipulation of pyruvate dehydrogenase kinase 4 (PDK4) to investigate its role in HG-associated ferroptosis.

RESULTS: HG-induced microglial ferroptosis, characterized by iron overload, elevated malondialdehyde and mitochondrial reactive oxygen species, glutathione peroxidase 4 (GPX4) downregulation, and mitochondrial damage, including loss of membrane potential and ultrastructural disintegration. This was accompanied by upregulated PDK4 expression. PDK4 overexpression attenuated ferroptosis by preserving GPX4, reducing lipid peroxidation, and maintaining mitochondrial integrity; these protective effects were reversed by n-6 polyunsaturated fatty acid (PUFA) supplementation. Conversely, PDK4 knockdown exacerbated ferroptosis via amplified n-6 PUFA synthesis and oxidative stress. Mechanistically, PDK4 acts as a metabolic gatekeeper by restricting acetyl-CoA availability for the synthesis of pro-ferroptotic PUFAs, thereby curtailing iron-dependent lipid peroxidation.

CONCLUSION: PDK4 is a critical regulator of HG-induced microglial ferroptosis, thereby bridging hyperglycemia-induced metabolic dysfunction and neurodegeneration. Our findings nominate PDK4 as a promising therapeutic target for diabetes-linked neurodegenerative diseases.},
}

*Ferroptosis/drug effects/physiology
Animals
*Glucose/pharmacology
Mice
*Microglia/metabolism/drug effects
Oxidative Stress/drug effects/physiology
*Fatty Acids, Unsaturated/biosynthesis/metabolism
*Pyruvate Dehydrogenase Acetyl-Transferring Kinase/metabolism
Lipid Peroxidation/drug effects
Reactive Oxygen Species/metabolism
Mitochondria/metabolism/drug effects

@article {pmid41342684,
year = {2025},
author = {Gierzynski, TF and Reader, JM and Flores, B and Fox-Fuller, JT and Gadwa, R and Bhaumik, A and Heidebrink, J and Giordani, B and Hampstead, BM and Bakulski, KM and Paulson, H and Roberts, JS and Rahman-Filipiak, A},
title = {Experiences of participant burden in an Alzheimer's disease research center longitudinal cohort.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251400787},
doi = {10.1177/13872877251400787},
pmid = {41342684},
issn = {1875-8908},
abstract = {BackgroundParticipant attrition can compromise the statistical power and generalizability of research results. Prior investigations have shown that perceptions of higher research burden are positively associated with participant withdrawal from longitudinal studies.ObjectiveWe measured participants' perceived burden in a cohort of older adult research participants enrolled in a longitudinal study of memory and aging at the Michigan Alzheimer's Disease Research Center (MADRC).MethodsParticipants completed a modified, 22-item version of the Perceived Research Burden Assessment (PeRBA), which quantitatively measures perceptions of research burden. We performed a multiple linear regression analysis to ascertain the associations between individual participant characteristics (e.g., demographic, clinical, and logistical/socioecological factors) and ratings of perceived research burden.ResultsA total of 300 participants completed the PeRBA. Overall burden was relatively low (mean = 36.6, SD = 9.38), with possible scores ranging from 22-110. Participants who self-identified as Black/African American reported significantly higher levels of perceived research burden relative to participants who self-identified as non-Hispanic White (β = 6.91, p < 0.001). Additionally, participants with a dementia diagnosis endorsed significantly higher levels of burden than their cognitively unimpaired counterparts (β = 4.85, p = 0.03). All other independent variables were not significantly associated with burden appraisal (p > 0.05).ConclusionsThe PeRBA is a useful tool for monitoring participant burden, as well as identifying differential levels of self-reported burden within research cohorts. These findings can inform tailored retention strategies that support the sustained engagement of participants, particularly those who may be the most susceptible to research burden.},
}

@article {pmid41342683,
year = {2025},
author = {Pozzi, FE and Spanio, A and Gallo, F and Isgrò, G and Remoli, G and Magi, A and Moscatelli, E and Crisci, E and Negro, G and Appollonio, I and Ferrarese, C and Tremolizzo, L},
title = {Cognitive and social intervention with Go and chess in early and subjective cognitive decline: The COGniChESs study results, with an updated meta-analysis.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251401481},
doi = {10.1177/13872877251401481},
pmid = {41342683},
issn = {1875-8908},
abstract = {BackgroundThere is a growing interest in dementia prevention and scalable cognitive enhancement strategies for individuals at-risk, with or without Alzheimer's disease. Board games have shown potential cognitive and mood benefits, but randomized controlled evidence remains limited and heterogeneous.ObjectiveWe aimed at assessing whether chess and/or Go could improve cognition, mood, and quality of life in individuals with mild cognitive impairment (MCI) and subjective cognitive decline (SCD).MethodsIndividuals with MCI or SCD aged ≥55 years were randomized to one of three arms: chess, Go (each consisting of 12 weekly group sessions), or a waitlist control group. Montreal Cognitive Assessment, digit span, trail making test, categorical fluency, Geriatric Depression Scale, and the World Health Organization Quality of Life scale were administered at baseline and follow-up. We also updated our previously published meta-analysis including these new results.Results69 subjects completed the study. Categorical fluency improved significantly in the games groups (p < 0.05). No between-group differences were found in overall cognition. A significant group × diagnosis × time interaction showed improved quality of life in MCI participants in the games groups (p = 0.002). A group × gender × time interaction revealed reduced depression in females in the games groups (p = 0.013). The updated meta-analysis confirmed a significant effect on depression (standardized mean differences -0.48, p = 0.013), but not on cognition.ConclusionsThe improvements in mood and quality of life, particularly among females and MCI subjects, underscore the psychological value of board games interventions, possibly through their social component. These activities may foster emotional well-being in older adults at risk for Alzheimer's disease, even without cognitive benefits.Clinicaltrials.gov Identifier: NCT06281652.},
}

@article {pmid41342682,
year = {2025},
author = {Stefanova, NA and Maksimova, KY and Tyumentsev, MA and Telegina, DV and Khodunova-Zhukovskaia, II and Rudnitsky, EA and Kolosova, NG},
title = {The early postnatal synapse assembly and expression profiles of synapse-related genes in a sporadic Alzheimer's disease-like pathology.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251396932},
doi = {10.1177/13872877251396932},
pmid = {41342682},
issn = {1875-8908},
abstract = {BackgroundRecent evidence suggests that prerequisites for Alzheimer's disease (AD) can form during prenatal and early postnatal development. These prerequisites have been identified to some extent in OXYS rats: a model of the sporadic form of AD.ObjectiveHere, we continue to study the role of delayed brain maturation in the development of the AD-like pathology much later in OXYS rats.MethodsWe assess synaptic-density changes and gene expression profiles in the prefrontal cortex (PFC) and hippocampus of OXYS and Wistar rats (parental strain; control) between ages "postnatal day 0" (P0) and P20.ResultsWe found that at birth, the synaptic population in the PFC of OXYS rats is half of that in Wistar rats. The proportion of both symmetric (inhibitory) contacts and asymmetric (excitatory) contacts in the hippocampus of OXYS rats at P14 and P20 matched these parameters in Wistar rats at P7 and P14, respectively. The transcriptome analysis of the PFC and hippocampus showed that gene expression profiles related to synapses are different between Wistar and OXYS rats. Next, we identified "age-specific" genes and "brain region-specific" genes whose changes in the expression can obviously contribute to the specific features of synapse formation in OXYS rats. Finally, analyses of cell-specific (neurons, astrocytes, microglia, oligodendrocytes, and endothelial cells) gene expression suggested that at P3-P20 in the PFC and hippocampus, more than 50% of downregulated genes are associated with glia: key regulators of neural-network functioning.ConclusionsCollectively, these data indicate a delay in the formation of interneuronal connections and in their efficiency in the OXYS strain.},
}

@article {pmid41342676,
year = {2025},
author = {Luca, A and Luca, M and Olgiati, P and Ferri, R and Serretti, A},
title = {Sex-specific sleep disturbances worsen psychiatric symptoms and cognitive decline in individuals with Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251400783},
doi = {10.1177/13872877251400783},
pmid = {41342676},
issn = {1875-8908},
abstract = {BackgroundThe possible association between sleep disturbances, neuropsychiatric symptoms and progression of cognitive decline considering sex still need to be clarified.ObjectiveThe aims of the study were to evaluate the possible associations between disturbed sleep (DS) and neuropsychiatric symptoms (NPS) and to evaluate the possible association between DS, cognitive decline progression and caregiver burden focusing on sex-differences.Methods184 participants were collected within the CATIE-AD trial. Based on the response given by the caregiver to the Neuropsychiatric Inventory, patients were classified into AD with disturbed sleep (AD-DS) or AD without disturbed sleep (ADwDS). Cognitive performance and NPS were evaluated. Progression was evaluated with the Δ-Mini-Mental State Examination (MMSE) (baseline MMSE-MMSE at 3-month follow-up). A sex stratified analysis was carried out.ResultsAD-DS performed worse than participants with ADwDS at all the cognitive tests. AD-DS presented more frequently depression, anxiety, aberrant motor behavior, disinhibition and eating disorders. At the sex-stratified analysis, AD-DS women were more frequently disinhibited and depressed than ADwDS. Men with AD-DS presented worse performances at several cognitive tests. Furthermore, various NPS were more frequent in men with AD-DS than in those with ADwDS, including hallucination, agitation, depression, and aberrant motor behavior. The burden was higher in caregivers of men belonging to the AD-DS group. Finally, at the linear regression, adjusting for age, education and MMSE at baseline, the presence of disturbed sleep was related to a more evident decline in MMSE in men (coeff. 2.5; 95%CI 0.72-4.29; p-value 0.006).ConclusionsDS was associated with several NPS, caregiver burden and, in men, faster cognitive decline progression.},
}

@article {pmid41342674,
year = {2025},
author = {Rabl, M and Zullo, L and Wehrli, J and Hössel, K and Lewczuk, P and Petkov Peyneshki, I and Seifritz, E and Klöppel, S and von Gunten, A and Popp, J},
title = {Omics-AD-A multimodal biomarker study on cognitive decline and neuropsychiatric symptoms: Design and cohort characteristics.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251401159},
doi = {10.1177/13872877251401159},
pmid = {41342674},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD) clinically manifests in cognitive decline and frequent neuropsychiatric symptoms (NPS).ObjectiveThe Omics-AD study's scope is to perform an in-depth multi-modal and longitudinal characterization of people with early AD to a) better understand pathophysiological changes of AD and b) identify new biomarkers for AD and AD-related clinical manifestation and progression, with a focus on NPS.MethodsParticipants in this prospective study were recruited at four Swiss memory-clinics. Comprehensive cognitive and neuropsychiatric assessments were performed at baseline and follow-up. Paired blood and cerebrospinal fluid (CSF) samples along with structural MRI were obtained at baseline. Established CSF AD biomarkers were analyzed. Untargeted omics and targeted molecular analyses will be performed and integrated in multi-modal, multi-omics data analysis.ResultsWe included 456 participants (mean age 71.2 years, 55.1% female), of which 48.5% were cognitively unimpaired (with no cognitive complains, NC, or with subjective cognitive decline, SCD) and 51.5% cognitively impaired (mild cognitive impairment, MCI, or mild clinical AD dementia). Half of the participants presented with NPS as measured by the Neuropsychiatric Inventory Questionnaire (48.5%) or the Mild Behavioral Impairment Checklist (52.7%). The most common symptoms were irritability (18%) and depression (17%). In total, 41.0% (n = 155) of participants were amyloid positive (20.6% of CN, 21.7% of SCD, 55.4% of MCI, and 72.4% of clinical AD dementia).ConclusionsThis multi-centric well-characterized cohort allows for single- and multi-omics analyses to investigate in depth molecular and biological pathway alterations in AD and their relationships with clinical manifestation and progression, with a particular focus on NPS.},
}

@article {pmid41342670,
year = {2025},
author = {Akaida, S and Katayama, O and Yamaguchi, R and Yamagiwa, D and Tomida, K and Shimada, H},
title = {The impact of involvement in social activities on dementia onset: The role of willingness.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251400782},
doi = {10.1177/13872877251400782},
pmid = {41342670},
issn = {1875-8908},
abstract = {BackgroundImplementing dementia prevention measures is a critical global health objective.ObjectiveThis study investigated the impact of social activity involvement and willingness on dementia onset in community-dwelling older adults, and potential differences across age and sex subgroups.MethodsLongitudinal analysis was conducted on 2247 community-dwelling older adults ≥65 years (mean age: 74) who participated in the National Center for Geriatric and Gerontology-Study of Geriatric Syndromes in Japan (2015-2016 baseline survey) and were followed up at onset of dementia, including Alzheimer's disease, over 60 months. The Lifestyle Activities Questionnaire was used to determine social activity involvement. Willingness to participate in social activities was determined by asking if participants were willing to engage in 12 specific activities. Participants were classified into three groups: low-involvement, high-involvement/low-willingness, and high-involvement/high-willingness. Statistical analysis was conducted using Cox proportional hazards analysis with dementia onset as the outcome variable, involvement and willingness groups as explanatory variables, and adjusted covariates. Subgroup analyses examined differences across age and sex groups.ResultsThe high-involvement/high-willingness group showed a significantly lower dementia incidence (p < 0.001) than the other groups. Cox proportional hazards analysis revealed that the high-involvement/high-willingness group had a significantly lower hazard ratio (HR: 0.73, 95% confidence interval: 0.54-0.97) for dementia onset than the low-involvement group. This result was maintained in men and the age > 75 group.ConclusionsHigher involvement and willingness to participate in social activities lowered dementia risk, while higher involvement but low-willingness showed no protective effect. This result was maintained in men and the age > 75 group.},
}

@article {pmid41342662,
year = {2025},
author = {Roque, NA and Hosgood, HD and Hall, CB},
title = {The importance of accurate indoor air quality assessment in the aging and dementia population.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251396928},
doi = {10.1177/13872877251396928},
pmid = {41342662},
issn = {1875-8908},
abstract = {As most persons spend most of their time indoors (>80% on most days), indoor air quality is potentially an important health concern, particularly in elderly populations at high risk for dementia. It is important to note that until recently, little attention has been given to indoor air quality and related standards; most regulatory thresholds remain limited to outdoor environments. Recognizing that the environments in which we live and work shape health, it is time to place indoor air quality at the center of brain health policy and research agendas, and to take intentional steps towards comprehensive in-home assessment.},
}

@article {pmid41342653,
year = {2025},
author = {Dybing, KM and Gao, S and Saykin, AJ and Risacher, SL and , },
title = {No significant associations between history of head injury and Alzheimer's disease fluid biomarkers in older adults.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251401201},
doi = {10.1177/13872877251401201},
pmid = {41342653},
issn = {1875-8908},
abstract = {BackgroundConcussions are gaining attention as a risk factor for Alzheimer's disease (AD). Previous reports suggest concussion, also called head injury (HI), may be associated with changes to AD biomarkers, including amyloid and tau. However, there has been little characterization of biofluid biomarkers in older adults with remote history of HI.ObjectiveWe investigated whether aging participants at risk for AD with self-reported HI history would demonstrate alterations to cerebrospinal fluid (CSF) and blood plasma biomarkers of AD.MethodsUsing two-way ANCOVAs and linear mixed effects models, we examined both baseline cross-sectional and longitudinal associations between HI history, cognition, and AD biofluid biomarkers in 100 participants with HI history compared to 2411 without HI history from the ADNI dataset.ResultsOn baseline analysis, participants with HI history had higher CSF Aβ42/40 ratios than non-HI participants. There were no other baseline differences in biomarkers between HI and non-HI participants, nor were there any main effects of HI upon longitudinal analysis. We observed consistent main effects of age and cognitive impairment that suggested a pattern of worsened AD biomarker signatures in impaired participants with increasing age.ConclusionsOur findings do not support an association between self-reported HI history and AD fluid biomarkers in older adults from the ADNI dataset. Further characterization of fluid biomarker trajectories both in the acute post-HI period and in participants with remote HI is needed to understand the temporal dynamics of fluid biomarkers after HI and the implications of HI for AD risk.},
}

@article {pmid41342652,
year = {2025},
author = {Talavera-Garza, L and Hirai, M and Hovey, JD},
title = {Social Engagement and Cognitive Function Among Older Mexican Heritage Latinos.},
journal = {Clinical gerontologist},
volume = {},
number = {},
pages = {1-15},
doi = {10.1080/07317115.2025.2596782},
pmid = {41342652},
issn = {1545-2301},
abstract = {OBJECTIVES: The current study examined the relationship between social engagement and cognitive function among older Mexican heritage Latinos in the U.S. Although social engagement has been identified as a factor that is protective against cognitive decline and dementia, its association with cognitive health in Mexican heritage Latinos is understudied.

METHODS: Data on cognitive health, social network characteristics, perceived social support, and social engagement were collected in a sample of older Mexican heritage Latinos in South Texas.

RESULTS: Social network characteristics, perceived social support, and social engagement were significantly correlated with cognitive health. A hierarchical multiple regression analysis was used to test the relative strength of these factors in predicting cognitive health, while controlling for relevant covariates. Social engagement was found to be a significant predictor of cognitive function, beyond the effects of perceived social support and social network characteristics.

CONCLUSIONS: Findings highlight social engagement as a modifiable behavioral factor that may support cognitive health in aging Mexican heritage Latinos.

CLINICAL IMPLICATIONS: The results suggest that screening for and enhancing social engagement may be a valuable clinical strategy for preserving cognitive function in older Latinos at risk of poor cognitive health outcomes.},
}

@article {pmid41342372,
year = {2025},
author = {Yuan, R and Liu, F and Yu, J},
title = {Gut microbiota-derived extracellular vesicles in Alzheimer's disease - Immunomodulatory mechanisms, biomarkers, and therapeutic opportunities: A review.},
journal = {Biomolecules & biomedicine},
volume = {},
number = {},
pages = {},
doi = {10.17305/bb.2025.13213},
pmid = {41342372},
issn = {2831-090X},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder that poses a growing global health challenge. Beyond traditional hallmarks such as amyloid-β (Aβ) deposition, tau hyperphosphorylation, and neuroinflammation, the gut-brain axis (GBA) has emerged as a significant modulator of AD pathogenesis. Among gut-derived mediators, microbiota-derived extracellular vesicles (mEVs) transport bioactive cargo across epithelial and vascular barriers, thereby linking intestinal dysbiosis to neurodegeneration. This narrative review synthesizes experimental, translational, and early clinical evidence regarding the immunomodulatory roles of gut mEVs in AD. We examine how mEVs may traverse compromised intestinal and blood-brain barriers, activate microglia and astrocytes, and influence Aβ and tau metabolism, thereby integrating peripheral and central immune interactions. Based on this evidence, we propose the "microbiota-EV-immune-neuro axis" as a conceptual framework that connects gut dysbiosis with AD-related neurodegeneration. The review also highlights emerging data on mEV signatures as minimally invasive biomarkers and explores their potential as therapeutic targets or delivery vectors. While current evidence is preliminary and methodologically heterogeneous, mEVs are increasingly recognized as both indicators and potential modulators of AD pathophysiology, emphasizing the need for standardized, longitudinal, and interventional studies.},
}

@article {pmid41342354,
year = {2025},
author = {Mieling, M and Wiskow, C and Bunzeck, N},
title = {Globus Pallidus Iron Relates to Cognitive Impairment in Alzheimer's Disease: Evidence From MRI-Based Meta-Analysis.},
journal = {Annals of the New York Academy of Sciences},
volume = {},
number = {},
pages = {},
doi = {10.1111/nyas.70078},
pmid = {41342354},
issn = {1749-6632},
support = {//University of Lübeck/ ; },
abstract = {Iron is essential for brain metabolism and cognitive functioning, but excessive levels during healthy and pathological aging can have detrimental effects. Although this notion was supported by several single studies, meta-analytic evidence in Alzheimer's disease (AD) is still scarce. Therefore, we performed a meta-analysis of 23 MRI experiments with, in total, 715 AD patients and 1130 healthy controls (HC). All studies employed iron sensitive markers in basal ganglia structures, thalamus, and hippocampus, together with the Mini-Mental-Status-Examination (MMSE) to quantify cognitive performance. In all regions of interest, significantly higher iron levels were present in people with AD compared to HC, with the most pronounced effects in the putamen followed by the caudate. Importantly, only globus pallidus iron levels were negatively correlated with MMSE performance in AD patients. Our results provide unique evidence that increases in iron levels, especially within basal ganglia structures, which provide a hub for cognitive information processing, are a characteristic hallmark of AD.},
}

@article {pmid41342337,
year = {2025},
author = {Bose, D and Mukherjee, A and Acharya, M and Choudhury, S and Ghosh, N},
title = {Artificial Intelligence for Detection of Parkinson's Disease From Speech Signals-A Comprehensive Review.},
journal = {BioFactors (Oxford, England)},
volume = {51},
number = {6},
pages = {e70065},
doi = {10.1002/biof.70065},
pmid = {41342337},
issn = {1872-8081},
mesh = {*Parkinson Disease/diagnosis/physiopathology ; Humans ; *Artificial Intelligence ; *Speech/physiology ; Electroencephalography ; Early Diagnosis ; Signal Processing, Computer-Assisted ; },
abstract = {After Alzheimer's disease, Parkinson's disease (PD) is the second most common neuropathological condition. It is a progressive degenerative disease at superannuation that affects the central nervous system (CNS) and slowly disable patients doing regular activities like walking, speaking, and writing. Early diagnosis of this disease helps to manage the patients and provide them therapy effectively. From the past few years, gait, electroencephalogram (EEG) signals and speech signals have been inspected to detect this disease at an early stage, out of which the most frequently considered one is speech signal, as it is reported by the researchers that 90% of the PD patients suffer from speech disorders. Also, speech signal analysis is a non-invasive and cost-effective method to detect PD at an early stage, and it helps to build telediagnosis models for prediction. Classical speech signal processing methodologies adopted in PD detection sometimes suffer from inadequate understanding of the effect of PD speech generation models and how that is reflected on speech signals captured from the PD patients. Artificial intelligence (AI) based methods attempts to learn those models from the given data in the best possible way to distinguish PD patients from the healthy controls. This paper's primary goal is to survey AI methodologies to detect PD using speech signals as reported in the publications between 2020 and 2024. As deep learning (DL) is a subset of machine learning (ML) and ML is a subset of AI, we consider 55 research publications related to ML and DL methods adopted for speech signal-based PD diagnosis. All the articles were published by IEEE and we have considered key words like "Machine learning approaches in Parkinson's disease detection from speech signals," "Application of Deep learning in Parkinson Disease detection from speech signals," "Artificial Intelligence in Parkinson's disease detection"; to find the articles reviewed in this study. This comprehensive review article reveals that both ML and DL algorithms have demonstrated encouraging outcomes, and the need of focused effort on more explainable AI based methods that can be clinically interpreted and hence potentially can be trusted for early diagnosis of Parkinson's disease.},
}

*Parkinson Disease/diagnosis/physiopathology
Humans
*Artificial Intelligence
*Speech/physiology
Electroencephalography
Early Diagnosis
Signal Processing, Computer-Assisted

@article {pmid41342327,
year = {2025},
author = {Su, H and Liu, Z and Wei, J and Liu, Y and Zhong, Y and Liu, X and Tan, C and Chen, L},
title = {PDK4 suppresses high glucose-induced microglial ferroptosis by restricting pro-ferroptotic PUFA biosynthesis.},
journal = {Neuroreport},
volume = {},
number = {},
pages = {},
doi = {10.1097/WNR.0000000000002234},
pmid = {41342327},
issn = {1473-558X},
abstract = {BACKGROUND: Diabetes significantly elevates the risk of neurodegenerative disorders, including Alzheimer's disease and Parkinson's disease, indicating shared pathophysiological mechanisms. While ferroptosis is increasingly implicated in neurodegeneration, microglia - highly vulnerable to ferroptosis - may mediate this link. However, it remains unknown whether high glucose (HG) directly induces microglial ferroptosis.

METHODS: Using HG-treated BV2 microglia, we integrated multiomics profiling (RNA-seq and targeted lipidomics), functional assays, and genetic manipulation of pyruvate dehydrogenase kinase 4 (PDK4) to investigate its role in HG-associated ferroptosis.

RESULTS: HG-induced microglial ferroptosis, characterized by iron overload, elevated malondialdehyde and mitochondrial reactive oxygen species, glutathione peroxidase 4 (GPX4) downregulation, and mitochondrial damage, including loss of membrane potential and ultrastructural disintegration. This was accompanied by upregulated PDK4 expression. PDK4 overexpression attenuated ferroptosis by preserving GPX4, reducing lipid peroxidation, and maintaining mitochondrial integrity; these protective effects were reversed by n-6 polyunsaturated fatty acid (PUFA) supplementation. Conversely, PDK4 knockdown exacerbated ferroptosis via amplified n-6 PUFA synthesis and oxidative stress. Mechanistically, PDK4 acts as a metabolic gatekeeper by restricting acetyl-CoA availability for the synthesis of pro-ferroptotic PUFAs, thereby curtailing iron-dependent lipid peroxidation.

CONCLUSION: PDK4 is a critical regulator of HG-induced microglial ferroptosis, thereby bridging hyperglycemia-induced metabolic dysfunction and neurodegeneration. Our findings nominate PDK4 as a promising therapeutic target for diabetes-linked neurodegenerative diseases.},
}

@article {pmid41342141,
year = {2025},
author = {Desai, R and John, A and Anderson, E and Stafford, J and Patel, AMR and Marchant, NL and Charlesworth, G and Zuber, V and Stott, J},
title = {Evidence for Causal Links Between Known Modifiable Risk Factors and Dementia: A Systematic Review of Mendelian Randomisation Studies.},
journal = {European journal of neurology},
volume = {32},
number = {12},
pages = {e70458},
doi = {10.1111/ene.70458},
pmid = {41342141},
issn = {1468-1331},
mesh = {Humans ; *Mendelian Randomization Analysis ; *Dementia/genetics/epidemiology ; Risk Factors ; Diabetes Mellitus, Type 2/epidemiology/genetics ; },
abstract = {BACKGROUND: We aimed to systematically review the evidence for associations between the known modifiable risk factors and dementia based on Mendelian randomisation (MR) studies.

METHOD: Five databases were searched from inception to April 2024 investigating the association between the 12 risk factors identified in the Lancet Commission and dementia. Evaluable analyses were categorized into one of four levels (robust, probable, suggestive, insufficient) based on estimate significance level and concordance of direction of effect between main and sensitivity analyses. Evidence from clinically diagnosed dementia outcomes was synthesized separately from proxy outcomes. A post hoc sensitivity analysis excluded estimates with concerns over construct validity.

RESULTS: A total of 47 studies were included, representing 240 MR associations (185 unique and evaluable). Over half (73.5%) of evaluable analyses were graded as providing insufficient evidence for a causal association. Among clinically diagnosed outcomes, the strongest evidence was for educational attainment (mainly probable evidence in a protective direction) and type 2 diabetes-related dysfunction (probable evidence in the risk direction). Smoking showed probable evidence of a protective association. Other risk factors, produced inconclusive or insufficient evidence. Proxy outcome analyses yielded weaker findings; in particular, the association between education and Alzheimer's disease reversed direction.

CONCLUSION: MR evidence for most Lancet Commission risk factors remains insufficient or inconclusive. The most consistent support for causal associations was observed for lower educational attainment and type 2 diabetes. Null findings should be interpreted cautiously given limitations in GWAS phenotyping, sample composition, and MR methodology.},
}

Humans
*Mendelian Randomization Analysis
*Dementia/genetics/epidemiology
Risk Factors
Diabetes Mellitus, Type 2/epidemiology/genetics

@article {pmid41342073,
year = {2025},
author = {Liu, Z and Meng, X and Lu, R and Meng, X and Li, S and Wang, Y and Liu, X and Liu, X and Liu, J},
title = {PBX1 Improves Cognition and Reduces Amyloid-β Pathology in APP/PS1 Mice by Transcriptionally Activating the CRTC2-CREB Pathway.},
journal = {Aging cell},
volume = {},
number = {},
pages = {e70311},
doi = {10.1111/acel.70311},
pmid = {41342073},
issn = {1474-9726},
support = {82073581//National Natural Science Foundation of China/ ; 82273673//National Natural Science Foundation of China/ ; 101832020CX277//Jilin University/ ; JJKH20250213BS//Jilin University/ ; 24GNYZ44//Jilin University/ ; MJR202510105//Medjaden Inc./ ; },
abstract = {Alzheimer's disease (AD) is characterized by progressive cognitive decline, amyloid β (Aβ) deposition, and synaptic dysfunction. However, the mechanisms underlying neurodegeneration remain poorly understood. In this study, we investigated the therapeutic potential of PBX1, a transcriptional regulator implicated in neurodevelopment and neuroprotection, against AD. PBX1 expression was significantly downregulated in postmortem hippocampal tissues from patients with AD and in the APP/PS1 mouse model. In vitro, PBX1a knockdown reduced neurite complexity and increased apoptosis. PBX1a overexpression reversed these effects and reduced soluble Aβ1-40 and Aβ1-42 levels. In vivo, hippocampal overexpression of PBX1a restored spatial learning and memory, reduced Aβ burden by 41%, and increased neurite length by 1.5-fold. These behavioral and structural improvements were accompanied by reduced levels of hyperphosphorylated Tau and toxic Aβ oligomers. Mechanistically, PBX1 directly activated the transcription of CRTC2-a coactivator of CREB, thereby increasing CRTC2 expression and its nuclear colocalization with phosphorylated CREB. Restoration of the PBX1-CRTC2-CREB axis enhanced neuronal survival and synaptic integrity. Notably, CRTC2 knockdown blocked PBX1-mediated reductions in Aβ deposition, apoptosis, and hyperphosphorylated Tau expression, confirming the role of the PBX1-CRTC2-CREB axis in conferring neuroprotection. Together, our findings indicate that PBX1 is a key modulator of neuronal resilience in AD and that it functions through transcriptional activation of the CRTC2/CREB pathway. By unraveling a mechanism that links transcriptional regulation to amyloid clearance and cognitive function, this study highlights PBX1 as a promising therapeutic target for AD.},
}

@article {pmid41342072,
year = {2025},
author = {Diniz, BS and Zhao, S and Drouard, G and Vuoksimaa, E and Ollikainen, M and Lenze, EJ and Xu, M and Fortinsky, RH and Kuchel, GA and Kaprio, J and Kuo, CL},
title = {Biological Aging Acceleration in Major Depressive Disorder: A Multi-Omics Analysis.},
journal = {Aging cell},
volume = {},
number = {},
pages = {e70310},
doi = {10.1111/acel.70310},
pmid = {41342072},
issn = {1474-9726},
support = {P30AG067988/AG/NIA NIH HHS/United States ; 100499//Academy of Finland/ ; 205585//Academy of Finland/ ; 118555//Academy of Finland/ ; 141054//Academy of Finland/ ; 264146//Academy of Finland/ ; 308248//Academy of Finland/ ; 307339//Academy of Finland/ ; 328685//Academy of Finland/ ; //Health Data Research UK/ ; //Office for National Statistics/ ; //UK Research and Innovation/ ; },
abstract = {Major depressive disorder (MDD) is linked to a higher risk of premature aging, but the mechanisms underlying this association remain unclear. Using data from two population cohorts (UK Biobank and Finnish Twin Cohort), we evaluate the relationship between systemic and organ-specific proteomic and epigenetic aging acceleration and MDD. A lifetime history of MDD was associated with accelerated proteomic aging at both systemic and organ-specific levels-including the brain-in both cohorts, with stronger associations than those observed with systemic epigenetic aging. Systemic and brain-specific proteomic aging acceleration were linked to higher risks of incident MDD and a greater risk of Alzheimer's disease, related dementia, and mortality among individuals with MDD in the UK Biobank. Evidence of depressive episode remission attenuated the association between MDD and systemic and brain-specific proteomic aging acceleration. Finally, Mendelian randomization analyses revealed a causal effect of MDD on systemic and brain-specific proteomic aging acceleration. Our results suggest a strong bidirectional association between MDD and biological aging acceleration. Biological aging acceleration, assessed by proteomic systemic and organ-specific clocks, can serve as a novel therapeutic target for treating MDD and for mitigating the long-term risks of adverse health outcomes associated with this condition.},
}

@article {pmid41342013,
year = {2025},
author = {Ortega, BA and Weisstaub, NV and Katche, C},
title = {Retrosplenial cortex 5-HT2A receptors critically contribute to recognition memory processing.},
journal = {Frontiers in cellular neuroscience},
volume = {19},
number = {},
pages = {1711777},
pmid = {41342013},
issn = {1662-5102},
abstract = {The anterior retrosplenial cortex (aRSC) functions as a hub that integrates multimodal sensory inputs into associative recognition memories. Although the aRSC receives dense serotonergic projections from the raphe nuclei, the role of serotonin in its function remains poorly understood. Among serotonergic receptors, 5-HT2A receptors (5-HT2ARs) are highly expressed in cortical regions, including the aRSC, and have been implicated in the modulation of cognitive processes. Based on our previous work demonstrating the involvement of the aRSC in recognition memory, here we investigated the contribution of 5-HT2ARs (memory) during different phases of the object recognition (OR) task in rats. We found that selective blockade of 5-HT2ARs in the aRSC differentially affected acquisition, consolidation, and retrieval. These findings identify 5-HT2ARs in the aRSC as critical modulators of recognition memory processing and suggest that their dysregulation could contribute to cognitive impairments observed in conditions such as Alzheimer's disease.},
}

@article {pmid41341968,
year = {2026},
author = {Hong, J and An, HK and Nam, H and Choi, J and Yu, SW},
title = {Presenilin 2 regulates corticosterone-induced autophagic death of adult hippocampal neural stem cells.},
journal = {Animal cells and systems},
volume = {30},
number = {1},
pages = {35-46},
pmid = {41341968},
issn = {1976-8354},
abstract = {Chronic psychological stress is a well-known risk factor for neurodegenerative diseases including Alzheimer disease (AD), yet the underlying mechanisms remain unclear. We previously showed that chronic stress impairs adult hippocampal neurogenesis by triggering autophagic cell death of adult hippocampal neural stem (HCN) cells. Impairment of adult hippocampal neurogenesis is widely observed in the brains of human AD patients and animal models. However, it remains unknown whether stress-induced death of HCN cells is related to the pathogenesis of AD. In this study, we investigated whether the stress hormone, corticosterone (CORT) induces HCN cell death through presenilin 2 (Psen2), a gene associated with familial AD. Using CRISPR/Cas9-based knockout models and in vitro CORT treatment, we found that Psen2 expression is upregulated by CORT and Psen2 deletion prevents CORT-induced death in HCN cells. However, the Psen2 N141I mutation, despite its pathogenicity in AD, did not exacerbate CORT-induced cell death in vitro and hippocampus-dependent behavioral deficits in vivo. These findings indicate that while Psen2 is essential for stress-induced death of HCN cells, the Psen2 N141I mutation alone may not be sufficient to link chronic stress to AD pathogenesis.},
}

@article {pmid41341742,
year = {2025},
author = {Ji, Q and Tang, E and Liao, Y and Yang, J and Wang, Y and Zhan, Y},
title = {Associations Between Nicotine Metabolites and Serum Neurofilament Light Chain Levels in the General Population.},
journal = {Chronic diseases and translational medicine},
volume = {11},
number = {4},
pages = {284-292},
pmid = {41341742},
issn = {2589-0514},
abstract = {BACKGROUND: Nicotine has been associated with cognitive functions such as memory and attention, with serum neurofilament light chain (sNfL) as a biomarker for neurological diseases such as Alzheimer's disease (AD) and multiple sclerosis (MS). However, the associations between nicotine and its metabolites and sNfL levels remain underexplored. This study aims to investigate the associations of serum and urine levels of cotinine and trans-3'-hydroxycotinine (hydroxycotinine) with sNfL levels in a broad population.

METHODS: Employing data from the National Health and Nutrition Examination Survey (NHANES) 2013-2014, this cross-sectional study applied multivariable linear regression models and restricted cubic splines to examine the links between cotinine, hydroxycotinine (both in serum and urine), and sNfL levels.

RESULTS: A total of 2052 participants were included in the serum analysis (mean age, 46.8 years; SD, 15.3; weighted 52.1% women) and 661 participants in the urine analysis (weighted 49.5% women). sNfL levels were positively associated with both serum and urine concentrations of cotinine and hydroxycotinine. Adjusted analyses revealed increases in sNfL levels in association with these substances, noting nonlinear associations for serum and urine cotinine and hydroxycotinine with sNfL levels.

CONCLUSION: These findings demonstrate robust positive associations between nicotine metabolites and sNfL levels and identify novel U-shaped associations at lower exposure levels. The results raise the hypothesis that very low nicotine metabolite levels may be associated with lower axonal injury markers, warranting further longitudinal and mechanistic studies to clarify causality.},
}

@article {pmid41341704,
year = {2025},
author = {Vishwasrao, P and Zengin, G and Sinan, KI and Minceva, M and Luca, SV},
title = {Supercritical CO2 extraction of hemp seeds: A multivariate perspective on the influence of processing parameters on oil composition, antioxidant activity, and enzyme inhibition.},
journal = {Food chemistry: X},
volume = {32},
number = {},
pages = {103296},
pmid = {41341704},
issn = {2590-1575},
abstract = {Hemp seeds are valued for their unique nutritional and health benefits. This study examined the impact of supercritical (sc)CO2 extraction conditions on hemp seed oil yield, composition, antioxidant activity, and enzyme inhibition using a multivariate approach. While pressure (300-500 bar) had minimal effects, temperature (40-60 °C) and ethanol addition (0.6-1.5 %) significantly influenced oil yield. The levels of fatty acids, tocopherols, carotenoids, chlorophylls, phenolics, and flavonoids varied independently of extraction pressure and temperature, but their extractability generally increased with ethanol concentration. The co-solvent addition also enhanced radical scavenging activity but diminished the metal-reducing and chelating properties. Hemp seed oils inhibited enzymes linked to chronic diseases like diabetes, skin disorders, and Alzheimer's. Multivariate analysis grouped samples by fatty acid profile, pigment content, and bioactivity. This work provides novel insights into how scCO2 conditions affect the chemical and biological properties of hemp seed oils.},
}

@article {pmid41341539,
year = {2025},
author = {Zhou, C and Peng, Y},
title = {Network Pharmacology and Molecular Docking Reveal Neuroprotective Potential of Ligusticum wallichii in Alzheimer's Disease Therapy.},
journal = {Neuropsychiatric disease and treatment},
volume = {21},
number = {},
pages = {2603-2622},
pmid = {41341539},
issn = {1176-6328},
abstract = {PURPOSE: In traditional Chinese medicine, Ligusticum wallichii is a prominent herb, acclaimed for its therapeutic roles, including anti-tumor, antioxidant, and anti-inflammatory benefits. Studies conducted recently suggest it may help reduce cognitive deficits linked to Alzheimer's disease. However, the precise neuroprotective pathways through which Ligusticum wallichii exerts its effects on Alzheimer's disease are not yet fully understood. Network pharmacology is utilized in this research to understand the mechanisms through which Ligusticum wallichii's active ingredient might protect against Alzheimer's disease.

METHODS: The TCMSP database was utilized to extract the bioactive compounds of Ligusticum wallichii, and their related molecular targets were identified. By querying the GeneCards and OMIM databases, targets associated with Alzheimer's disease were identified. Using Cytoscape 3.8.2, a regulatory network mapping the interactions between active compounds and their respective targets was constructed. A protein-protein interaction network was generated by analyzing the target genes influenced by Ligusticum wallichii in Alzheimer's disease using the String database. The DAVID database was utilized to perform functional enrichment analysis, encompassing Gene Ontology (GO) and KEGG pathway analyses, to identify possible biological pathways related to these targets. Following this, molecular docking studies were carried out to confirm the interaction strength of the active compounds to the pivotal targets. Finally, in vitro experimental validation was performed to corroborate the findings.

RESULTS: Seven bioactive compounds were identified from Ligusticum wallichii, interacting with 269 potential targets. Molecular docking revealed that Myricanone, Mandenol, and Sitosterol exhibited stable binding affinities with STAT3, HSP90AA1, and EGFR, with binding energies ranging from -4.04 to -5.87 kcal/mol. In vitro studies demonstrated that these compounds significantly downregulated the expression of STAT3, EGFR, and HSP90AA1 in Neuro 2A cells.

CONCLUSION: In conclusion, the results indicate that Ligusticum wallichii significantly downregulated STAT3, EGFR, and HSP90AA1 expression in Neuro 2A cells, providing mechanistic evidence that targeting these proteins may ameliorate neurodegenerative processes in Alzheimer's disease and highlighting Ligusticum wallichii's promising therapeutic potential.},
}

@article {pmid41341510,
year = {2025},
author = {Yang, J and Yang, F and Chen, G and Liu, M and Yuan, S and Zhang, TE},
title = {Receptor-mediated mitophagy: a new target of neurodegenerative diseases.},
journal = {Frontiers in neurology},
volume = {16},
number = {},
pages = {1665315},
pmid = {41341510},
issn = {1664-2295},
abstract = {Neurodegenerative diseases are a category of neurological conditions with high prevalence that pose major treatment challenges. Common pathologies involve protein accumulation and mitochondrial damage. Mitophagy maintains cellular homeostasis by removing defective mitochondria, which are associated with the pathogenesis of neurodegenerative diseases. Although the ubiquitin-dependent mitophagy mediated by the PINK1-Parkin pathway has been extensively studied, growing evidence indicates that receptor-mediated mitophagy plays a crucial compensatory role in neurons, particularly when the PINK1-Parkin pathway is impaired. This review focuses on the emerging field of receptor-mediated mitophagy, systematically elaborating its role as a key homeostatic mechanism operating independently of the canonical PINK1/Parkin pathway. It provides a focused analysis of the specific functions and activation mechanisms of key receptors-including BNIP3, NIX, FUNDC1, and AMBRA1-in models of Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Furthermore, this review explores the clinical potential of targeting these specific receptors for precise intervention, aiming to provide a new theoretical foundation and direction for developing therapeutic strategies against neurodegenerative diseases.},
}

@article {pmid41341423,
year = {2025},
author = {Varghese, A and Fajardo, AR and Gowda Parameshwara, P and Thankappan, M and Kannan, B},
title = {Improving Alzheimer Disease Diagnosis via a Custom Convolutional Neural Network and Pretrained Models: Development and Evaluation of a Diagnostic Tool (NeuroFusionNet).},
journal = {JMIR neurotechnology},
volume = {4},
number = {},
pages = {e68839},
pmid = {41341423},
issn = {2817-092X},
abstract = {BACKGROUND: Alzheimer disease (AD) is a progressive neurodegenerative disorder that impairs cognitive function, memory, and behavior. Early and accurate diagnosis is essential for effective management; however, traditional cognitive tests often lack the sensitivity and specificity required for early detection.

OBJECTIVE: This study aims to develop and evaluate NeuroFusionNet-a diagnostic tool that integrates a custom convolutional neural network (CNN) with a pretrained VGG16 model-to improve the accuracy and reliability of AD diagnosis from neuroimaging data across multiple cognitive classes.

METHODS: A comprehensive preprocessing pipeline, including brain region segmentation, was implemented to isolate regions of interest and reduce noise. NeuroFusionNet extracts multilevel features by combining a custom CNN with VGG16, while Local Interpretable Model-Agnostic Explanations enhances interpretability. Data were obtained from the Alzheimer's Disease Neuroimaging Initiative database, comprising 600 test samples (120 per class for AD, cognitively normal, early mild cognitive impairment, late mild cognitive impairment, and mild cognitive impairment). Given the multiclass nature of the study, odds ratios were not applied. Statistical significance was assessed using the McNemar test for paired predictions.

RESULTS: NeuroFusionNet achieved an overall accuracy of 0.81 (95% CI 0.779-0.841; P<.001). Per-class performance metrics were as follows: AD: precision 0.90 (95% CI 0.85-0.95), recall 0.78 (95% CI 0.72-0.84), F 1-score 0.84; cognitively normal: precision 0.67 (95% CI 0.60-0.74), recall 0.97 (95% CI 0.94-1.00), F 1-score 0.79; early mild cognitive impairment: precision 0.90 (95% CI 0.84-0.96), recall 0.82 (95% CI 0.76-0.88), F 1-score 0.86; late mild cognitive impairment: precision 0.95 (95% CI 0.90-1.00), recall 0.87 (95% CI 0.81-0.93), F 1-score 0.90; and mild cognitive impairment: precision 0.71 (95% CI 0.64-0.78), recall 0.61 (95% CI 0.53-0.69), F 1-score 0.65. Training and validation curves over 50 epochs indicated robust learning with minimal overfitting.

CONCLUSIONS: NeuroFusionNet demonstrated robust performance in a multiclass diagnostic setting, achieving high accuracy and balanced per-class performance. The combination of a custom CNN and fine-tuned VGG16, along with the interpretability provided by Local Interpretable Model-Agnostic Explanations, yields a reliable tool for early AD detection with significant potential to enhance clinical decision-making. Further validation on larger datasets is warranted.},
}

@article {pmid41341281,
year = {2025},
author = {Li, C and Sheng, Z and Cohen, T and Pakhomov, S},
title = {"Is There Anything Else?": Examining Administrator Influence on Linguistic Features from the Cookie Theft Picture Description Cognitive Test.},
journal = {... Workshop on Cognitive Modeling and Computational Linguistics. Workshop on Cognitive Modeling and Computational Linguistics},
volume = {2025},
number = {},
pages = {91-103},
pmid = {41341281},
abstract = {Alzheimer's Disease (AD) dementia is a progressive neurodegenerative disease that negatively impacts patients' cognitive ability. Previous studies have demonstrated that changes in naturalistic language samples can be useful for early screening of AD dementia. However, the nature of language deficits often requires test administrators to use various speech elicitation techniques during spontaneous language assessments to obtain enough propositional utterances from dementia patients. This could lead to the "observer's effect" on the downstream analysis that has not been fully investigated. Our study seeks to quantify the influence of test administrators on linguistic features in dementia assessment with two English corpora the "Cookie Theft" picture description datasets collected at different locations and test administrators show different levels of administrator involvement. Our results show that the level of test administrator involvement significantly impacts observed linguistic features in patient speech. These results suggest that many of significant linguistic features in the downstream classification task may be partially attributable to differences in the test administration practices rather than solely to participants' cognitive status. The variations in test administrator behavior can lead to systematic biases in linguistic data, potentially confounding research outcomes and clinical assessments. Our study suggests that there is a need for a more standardized test administration protocol in the development of responsible clinical speech analytics frameworks.},
}

@article {pmid41341242,
year = {2024},
author = {Gutman, B and Shmilovitch, AH and Aran, D and Shelly, S},
title = {Twenty-Five Years of AI in Neurology: The Journey of Predictive Medicine and Biological Breakthroughs.},
journal = {JMIR neurotechnology},
volume = {3},
number = {},
pages = {e59556},
pmid = {41341242},
issn = {2817-092X},
abstract = {Neurological disorders are the leading cause of physical and cognitive disability across the globe, currently affecting up to 15% of the world population, with the burden of chronic neurodegenerative diseases having doubled over the last 2 decades. Two decades ago, neurologists relying solely on clinical signs and basic imaging faced challenges in diagnosis and treatment. Today, the integration of artificial intelligence (AI) and bioinformatic methods is changing this landscape. This paper explores this transformative journey, emphasizing the critical role of AI in neurology, aiming to integrate a multitude of methods and thereby enhance the field of neurology. Over the past 25 years, integrating biomedical data science into medicine, particularly neurology, has fundamentally transformed how we understand, diagnose, and treat neurological diseases. Advances in genomics sequencing, the introduction of new imaging methods, the discovery of novel molecular biomarkers for nervous system function, a comprehensive understanding of immunology and neuroimmunology shaping disease subtypes, and the advent of advanced electrophysiological recording methods, alongside the digitalization of medical records and the rise of AI, all led to an unparalleled surge in data within neurology. In addition, telemedicine and web-based interactive health platforms, accelerated by the COVID-19 pandemic, have become integral to neurology practice. The real-world impact of these advancements is evident, with AI-driven analysis of imaging and genetic data leading to earlier and more accurate diagnoses of conditions such as multiple sclerosis, Parkinson disease, amyotrophic lateral sclerosis, Alzheimer disease, and more. Neuroinformatics is the key component connecting all these advances. By harnessing the power of IT and computational methods to efficiently organize, analyze, and interpret vast datasets, we can extract meaningful insights from complex neurological data, contributing to a deeper understanding of the intricate workings of the brain. In this paper, we describe the large-scale datasets that have emerged in neurology over the last 25 years and showcase the major advancements made by integrating these datasets with advanced neuroinformatic approaches for the diagnosis and treatment of neurological disorders. We further discuss challenges in integrating AI into neurology, including ethical considerations in data use, the need for further personalization of treatment, and embracing new emerging technologies like quantum computing. These developments are shaping a future where neurological care is more precise, accessible, and tailored to individual patient needs. We believe further advancements in AI will bridge traditional medical disciplines and cutting-edge technology, navigating the complexities of neurological data and steering medicine toward a future of more precise, accessible, and patient-centric health care.},
}

@article {pmid41341187,
year = {2025},
author = {Wang, Z and Xia, K and Huang, X and Fan, D and Yang, Q},
title = {Amyloid marker levels and the risk of developing cerebral small vessel disease: A Mendelian randomization study.},
journal = {Journal of Alzheimer's disease reports},
volume = {9},
number = {},
pages = {25424823251403565},
pmid = {41341187},
issn = {2542-4823},
abstract = {BACKGROUND: Previous observational studies have suggested a potential association between amyloid marker levels and the risk of developing cerebral small vessel disease (CSVD), but this relationship remains incompletely understood.

OBJECTIVE: This study was conducted to assess the impact of amyloid marker levels on the risk of developing CSVD via Mendelian randomization (MR) design.

METHODS: Using the latest genome-wide association study summary statistics for 5 plasma amyloid markers and 4 CSVD traits, a two-sample MR study was conducted to assess the genetic relationship between amyloid marker levels and CSVD risk. Furthermore, reverse MR analysis was utilized to establish the causal relationship between CSVD traits and the levels of the identified plasma amyloid markers to explore potential bidirectional causality.

RESULTS: After FDR correction, greater amyloid-β (Aβ) 42 levels were associated with an increased risk of developing lobar cerebral microbleeds (CMBs) (odds ratio = 2.311, 95% confidence interval 1.403-3.809, p = 0.001, p FDR = 0.040). Potential positive correlations were detected between Aβ40 levels and the risk of developing intracerebral hemorrhage, between Aβ42 levels and the risk of developing all CMBs, and between serum amyloid P component levels and white matter fractional anisotropy status. In reverse MR analysis, no effect of CSVD traits on amyloid marker levels was detected.

CONCLUSIONS: Our study suggests potential causal relationships between amyloid marker levels and different CSVD traits. Our results contribute to a greater understanding of the pathophysiology of CSVD, particularly in relation to amyloid deposition.},
}

@article {pmid41341151,
year = {2025},
author = {Bouter, Y and Glasnek, RM and Wenzel, JM and Bouter, C},
title = {[18]F-FDG-PET and Multimodal Biomarker Integration: A Powerful Tool for Alzheimer's Disease Diagnosis.},
journal = {Nuclear medicine and molecular imaging},
volume = {59},
number = {6},
pages = {453-471},
pmid = {41341151},
issn = {1869-3474},
abstract = {UNLABELLED: An early, biomarker-based diagnosis of Alzheimer's Disease (AD) is crucial, especially with the emerging availability of novel therapeutic options. However, the role of [18]F-FDG-PET and its relationship to other PET and CSF biomarkers remains unclear. Therefore, the aim of this study was the evaluation of the role of [18]F-FDG-PET in AD diagnosis and its relationship to other commonly used fluid and PET biomarkers and their individual and multimodal accuracy in AD diagnosis. We included n = 157 AD patients, n = 603 MCI patients, and n = 380 cognitively normal participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) that underwent PET imaging with [18]F-FDG or [18]F-Florbetapir. Clinical and imaging data including patient characteristics, CSF biomarkers, cognition tests, [18]F-FDG-PET, [18]F-Florbetapir-PET, and [18]F-Flortaucipir-PET were retrospectively analyzed. PET images were quantified in several brain regions. The uptake of [18]F-FDG was inversely correlated with [18]F-Florbetapir and positively correlated with CSF Aβ42 in several brain regions commonly affected by AD. Additionally, [18]F-FDG uptake showed an inverse correlation with both forms of CSF tau, t-tau and p-tau, in various brain regions, but did not correlate with [18]F-Flortaucipir uptake. Moreover, regional [18]F-FDG uptake was positively correlated with cognitive function. Diagnostic accuracies were similarly high for [18]F-FDG uptake in the PCC/Precuneus region, [18]F-Florbetapir uptake, CSF Aβ42, CSF p-tau, and [18]F-Flortaucipir uptake in differentiating AD from cognitively normal individuals. [18]F-FDG-PET and its combination with CSF p-tau/ Aβ42 ratio showed the highest predictive power for disease severity. The study underscores the potential of integrating [18]F-FDG-PET with CSF biomarkers to enhance the diagnosis, prognosis, and monitoring of AD, highlighting the complexity and regional specificity of biomarker interactions in neurodegeneration.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13139-025-00932-2.},
}