@article {pmid41358223,
year = {2025},
author = {Kong, Y and Xu, Z and Zhu, Z and Ye, L and Zhou, S},
title = {A mixed-methods study on collaborative health governance for older adults with mild cognitive impairment in Hangzhou, China.},
journal = {Frontiers in public health},
volume = {13},
number = {},
pages = {1720145},
pmid = {41358223},
issn = {2296-2565},
mesh = {Humans ; *Cognitive Dysfunction/therapy ; China ; Aged ; Female ; Male ; Independent Living ; Aged, 80 and over ; *Cooperative Behavior ; Social Isolation/psychology ; Middle Aged ; Social Support ; },
abstract = {INTRODUCTION: Mild cognitive impairment (MCI), a prodromal stage of Alzheimer's disease, poses a critical public health challenge in aging populations. Current community-based MCI interventions are often fragmented, lacking effective collaboration among families, community workers, and physicians. This study aimed to construct a multi-agent collaborative governance model and propose optimization strategies for community-based MCI management.

METHODS: A mixed-methods design was employed in Hangzhou, China. Quantitatively, 373 community-dwelling older adults with MCI completed the Family APGAR Index, Social Isolation Scale, and Mini-Mental State Examination (MMSE). Structural equation modeling (SEM) was used to analyze the pathways linking social isolation, family support, and cognitive domains. Qualitatively, thematic analysis was conducted on in-depth interviews with four community workers and four family physicians to delineate stakeholder responsibilities and collaboration challenges.

RESULTS: The quantitative results revealed a dual effect of family support: it was positively associated with memory and calculation ability (path coefficient = 0.176, p < 0.05) but negatively associated with reading and praxis ability (path coefficient = -0.164, p < 0.05). Reduced social isolation significantly enhanced family support (β = 0.405, p < 0.001). Furthermore, positive feedback loops were identified among cognitive domains (orientation, reading/praxis, memory/calculation). Qualitatively, key barriers included the absence of structured collaboration mechanisms, passive information-sharing, and insufficiently trained family caregivers.

DISCUSSION AND CONCLUSION: This study underscores the complex role of family support and the necessity of integrated care. We propose a tripartite "Social Worker-Physician-Family" collaborative framework, featuring skill-building curricula, psychological support, and cross-sectoral data linkage protocols to optimize health outcomes. However, due to the cross-sectional design, causal inferences are limited, and longitudinal studies are needed to validate the pathways. The findings offer empirical evidence and practical insights for designing community-based interventions for early-stage cognitive impairment in aging societies.},
}

Humans
*Cognitive Dysfunction/therapy
China
Aged
Female
Male
Independent Living
Aged, 80 and over
*Cooperative Behavior
Social Isolation/psychology
Middle Aged
Social Support

@article {pmid41357966,
year = {2025},
author = {Graham, UM and Pinto, JM and Weuve, J and Dozier, AK and Rogers, R and Nag, S and Schneider, J and Kaufman, JD and Bennett, DA and Oberdörster, G},
title = {Nose-to-brain translocation of inhaled ultrafine elongated particles: facts and mysteries.},
journal = {Frontiers in toxicology},
volume = {7},
number = {},
pages = {1655149},
pmid = {41357966},
issn = {2673-3080},
abstract = {In this study, we report that inhaled nanosized elongated mineral particles (EMPs) reach the human central nervous system (CNS) via two neuronal pathways, cranial nerve I (olfactorius) and cranial nerve V (trigeminus), from deposits on the nasal mucosa. High-resolution analytical imaging of autopsied brain tissues from eleven members of a Religious Orders Study (ROS) cohort (Rush Alzheimer's Disease Center) indicated that EMPs translocate from their nasal deposits to the brain either by the olfactory pathway (presence in the olfactory bulb (OB), olfactory tract, and amygdala) or by the trigeminal pathway (presence in the cerebellum). Sub-nanometer imaging and immunohistochemical (IHC) labeling were used to detect corpora amylacea (CA), abundant numbers of endogenous ferritin nanoparticles, and myelin damage as indicators of inflammation or oxidative stress. The majority of EMPs in the OB were identified as inorganic crystalline and amorphous SiO2 fibers. Amphibole-like fibers (Mg/Si/Fe) were present (length from 25 up to 200 nm), along with lengthened nanoplastics and metallic or carbonaceous fibers. Extensive and consistent demyelination, phosphorylation, wall thickening, and CA bodies (size ranging from 10 nm to ∼10 μm) are present in all studied brain tissues. EMPs are frequently observed inside and outside of CA bodies that occur in close proximity to neurons with myelin damage. The majority of EMPs show shedding of nanosized fiber fragments and ions from their long fiber surfaces and the formation of carbon-rich coronas (physiochemical alterations: bioprocessing). Similar to spherical nanoparticles, EMPs show a tendency to bioprocess, which involves interacting with microglia, astrocytes, and CA. In conclusion, we note that although the presence of ambient EMPs in the OB, amygdala, and cerebellum of human brains is consistent with neuronal translocation from nasal deposits of inhaled EMPs to the human CNS, it remains important to further investigate the potential contribution of nano-EMPs entering from the blood compartment by crossing the blood-brain barrier (BBB) and other potential routes to the CNS.},
}

@article {pmid41357770,
year = {2025},
author = {Kang, J and Kang, H and Seo, JH},
title = {CNN-based framework for Alzheimer's disease detection from EEG via dynamic mode decomposition.},
journal = {Frontiers in neuroinformatics},
volume = {19},
number = {},
pages = {1706099},
pmid = {41357770},
issn = {1662-5196},
abstract = {Alzheimer's disease (AD) and frontotemporal dementia (FTD) are major neurodegenerative disorders with characteristic EEG alterations. While most prior studies have focused on eyes-closed (EC) EEG, where stable alpha rhythms support relatively high classification performance, eyes-open (EO) EEG has proven particularly challenging for AD, as low-frequency instability obscures the typical spectral alterations. In contrast, FTD often remains more discriminable under EO conditions, reflecting distinct neurophysiological dynamics between the two disorders. To address this challenge, we propose a CNN-based framework that applies Dynamic Mode Decomposition (DMD) to segment EO EEG into shorter temporal windows and employs a 3D CNN to capture spatio-temporal-spectral representations. This approach outperformed not only the conventional short-epoch spectral ML pipeline but also the same CNN architecture trained on FFT-based features, with particularly pronounced improvements observed in AD classification. Excluding delta yielded small gains in AD-involving contrasts, whereas FTD/CN was unchanged or slightly better with delta retained-suggesting delta is more perturbative in AD under EO conditions.},
}

@article {pmid41357743,
year = {2025},
author = {Silva-Pérez, M and Chin, J},
title = {Super-Fast, Super-Early: High-Frequency Oscillations May Be a Prelude to Alzheimer's Dementia in Down Syndrome.},
journal = {Epilepsy currents},
volume = {},
number = {},
pages = {15357597251404966},
pmid = {41357743},
issn = {1535-7597},
}

@article {pmid41357423,
year = {2025},
author = {Babulal, GM and Blake, M and Chen, C and Zhu, Y and Pal, S and Brown, DC},
title = {Operationalizing passive sensors into scalable, reproducible, neurobehavioral digital markers for Alzheimer's disease: Lessons learned over 10 years.},
journal = {Digital health},
volume = {11},
number = {},
pages = {20552076251404502},
pmid = {41357423},
issn = {2055-2076},
}

@article {pmid41357417,
year = {2025},
author = {Roy, A and Kumar, D and Bhattacharya, P and Borah, A},
title = {In silico decoding strategic pathways inhibition by coptisine for halting Alzheimer's pathology: a mechanistic insight.},
journal = {In silico pharmacology},
volume = {13},
number = {3},
pages = {202},
pmid = {41357417},
issn = {2193-9616},
abstract = {Alzheimer's Disease (AD) is a brain disorder with various neuropathological hallmarks and has become a major concern globally due to limited therapeutic options. Cholinergic dysfunction due to the depletion of acetylcholine (ACh) levels in the synapse caused by increased acetylcholinesterase (AChE) activity is one of the major factors that drives AD progression. AChE also accelerates amyloid beta (Aβ) formation and leads to amyloid plaque deposition in the brain. Production of Aβ from amyloid precursor protein (APP) with sequential cleavage by β-secretase (BACE1) and γ-secretase causes severe brain damage due to plaque toxicity. Neurofibrillary tangles (NFTs), a neuronal catastrophe resulting from hyperphosphorylation of tau protein due to upregulation of glycogen synthase kinase 3 beta (GSK3β) and downregulation of Wnt signaling because of Dickkopf-1 and low density lipoprotein receptor-related protein 6 (DKK1-LRP6) interaction, are a major pathogenic event in AD. Recent research has increasingly focused on targeting amyloidopathy, tauopathy, and cholinergic pathways as therapeutic strategies for mitigating AD pathology. Coptisine, a bioactive alkaloid having enormous pharmacological properties, including neuroprotective action, is considered in our in-silico investigation. Collective inhibition of key targets in AD pathogenesis, like AChE, β-secretase (BACE1), γ-secretase, GSK3β, and DKK1-LRP6 interaction, could be a positive approach in the arsenal of Alzheimer's treatment. In this article, we report that coptisine can inhibit these five major targets as evident from our molecular docking study, and propose it as a potential multi-target drug to play a key role in halting AD pathology. Further, comparative analysis based on predicted values of cheminformatics and pharmacokinetic profiling of coptisine and known inhibitors increases its possibility to ameliorate AD. However, robust research, including a preclinical and clinical study on coptisine for its safety and efficacy assessment against AD pathology, is warranted for its validation as an anti-AD drug.},
}

@article {pmid41357353,
year = {2025},
author = {Schroeter, ML and Girbardt, J and Luck, T and Rodriguez, FS and Plant, GT and Wicklein, B and Wirkner, K and Engel, C and Kynast, J and Girbardt, C and Wang, M and Polyakova, M and Hinz, A and Witte, AV and Kirsten, T and Loeffler, M and Villringer, A and Riedel-Heller, SG and Elze, T and Rauscher, FG},
title = {Retinal nerve fibre layer thickness is associated with attention and predicts risk states of dementia.},
journal = {Brain communications},
volume = {7},
number = {6},
pages = {fcaf464},
pmid = {41357353},
issn = {2632-1297},
abstract = {Alzheimer's disease is associated with lower circumpapillary retinal nerve fibre layer thickness (cpRNFLT). It remains unclear if dementia risk states, i.e. mild cognitive impairment (MCI) and mild neurocognitive disorder (NCD) might associate with cpRNFLT and whether specific domains of cognitive function are related. The present study compared systematically all cognitive domains as defined in the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) with pointwise analyses of the cpRNFLT and whether cpRNFLT variation can predict MCI and mild NCD. Spectral domain optical coherence tomography scans (768 A-scans of cpRNFLT) were analysed from 1300 participants with reliable measurements, without eye diseases, and further exclusion due to brain disorders. The study was conducted in the framework of the population-based Leipzig Research Centre for Civilization Diseases-(LIFE)-Adult study. The six DSM-5 domains were operationalized by means of both (sub-)scales of the 'Consortium to Establish a Registry for Alzheimer Disease' (CERAD-Plus) neuropsychological test battery and the 'Reading the Mind in the Eyes' test. Age, sex, education and scanning radius were used as additional regressors to adjust for demographics and eye anatomy. 2133 eyes of 1300 subjects were selected (age range 60-79 years). After adjustment for multiple comparisons, in the domain 'attention', worse performance was related to significantly thinner cpRNFL, especially in male participants, most pronounced for temporal and nasal-superior locations. For the domain 'executive function' significantly thicker cpRNFL was found nasally in female participants. There were no significant (P < 0.05) cpRNFLT locations for the DSM-5 domains 'learning/memory', 'perceptual-motor abilities', 'language' and 'social cognition'. Subjects with MCI had thinner cpRNFL temporal-superior compared to subjects with normal cognition. Furthermore, alterations of cpRNFLT in MCI and mild NCD, and subgroups amnestic MCI and amnestic mild NCD existed, for the latter mainly in temporal regions. Compared to cognitively unimpaired, analyses revealed hippocampal volume decreases in MCI and mild NCD groups, and comparable white matter lesion volume, compatible with Alzheimer aetiology. cpRNFL fibre thinning was most prominently associated with lower performance in the attention domain. Highly location specific thinning involved predominantly retinal locations superior and temporal to the optic disc. Thinning in temporal-superior segment was associated with MCI. Temporal thinning indicated amnestic MCI and amnestic mild NCD. Executive function, MCI, and mild NCD presented a concordantly negative association of cognition and RNFLT nasally. As cpRNFLT is obtained conveniently within seconds, our results might assist clinicians by earlier identification of patients at risk for developing cognitive decline associated with diseases like Alzheimer's disease.},
}

@article {pmid41357351,
year = {2025},
author = {Tripathy, S and Miller, GN and Cohen, AL},
title = {Network localization of altered auditory and somatosensory sensitivity based on causal brain lesions.},
journal = {Brain communications},
volume = {7},
number = {6},
pages = {fcaf463},
pmid = {41357351},
issn = {2632-1297},
abstract = {Sensory processing as a neurological construct is the perception and interpretation of sensory information from both the body and the environment. Disruptions to sensory processing adversely impact daily functioning. One type of disruption that is particularly interesting is altered sensory modulation, leading to hypersensitivity or hyposensitivity, which are common in many neurodevelopmental and psychiatric conditions such as autism spectrum disorder, attention-deficit/hyperactivity disorder, Alzheimer's, and schizophrenia. Here we aim to identify modality-specific and cross-modality brain networks involved in altered auditory and somatosensory processing. A systematic review identified 61 patients with new-onset sensory alterations following focal brain injury. Lesions were traced and combined with resting-state data from 1000 healthy controls to generate normative lesion connectivity maps. The specificity of our cohort's lesion-connectivity compared to lesions associated with 22 other neuropsychiatric symptoms was assessed with voxel-wise two-sample t-tests performed with the FSL Permutation Analysis of Linear Models tool (family-wise error P < 0.05). A conjunction analysis against lesions associated with hallucination was conducted by binarizing and multiplying one-sample T-test maps to identify common lesion-connections between the conditions. Modality-specific networks were connected to their unimodal cortices and the cerebellum. Overall, lesions associated with cross-modality sensitivity changes had convergent connections to the substantia nigra, medial orbitofrontal cortex, and cerebellum (Lobule V, medial Lobule VIIIa). Subgroup analysis by direction revealed that lesions causing decreased sensitivity were connected to lobule X, in addition to the aforementioned cerebellar regions, while those causing increased sensitivity were only connected to medial V and bilateral V. Regardless of directionality, 90% of lesions exhibited connections to bilateral Lobule V. Conjunction analysis with hallucinations revealed common lesion-connections to cerebellar vermis and frontal pole. Our analysis identified significant lesion-connections to the substantia nigra, medial orbitofrontal cortex, and cerebellum-highlighting these key regions in cross-modality sensory processing. These findings emphasize the role of higher cognitive functions in sensory integration and suggest potential targets for neuromodulation to improve sensory processing.},
}

@article {pmid41357333,
year = {2025},
author = {Wu, CY and Reynolds, WC and Abril, I and McManus, AJ and Brenner, C and González-Irizarry, G and Gutiérrez-Martínez, L and Sun, O and Rosand, J and Tanzi, RE and Arnold, SE and Guzmán-Vélez, E},
title = {Effects of nicotinamide riboside on NAD+ levels, cognition, and symptom recovery in long-COVID: a randomized controlled trial.},
journal = {EClinicalMedicine},
volume = {89},
number = {},
pages = {103633},
pmid = {41357333},
issn = {2589-5370},
abstract = {BACKGROUND: Long-COVID often involves cognitive difficulties, immune dysregulation, and mitochondrial dysfunction. Studies suggest nicotinamide adenine dinucleotide (NAD+) precursors like nicotinamide riboside (NR) may reduce inflammation and support mitochondrial and neurological function. This double-blind, placebo (PBO)-controlled clinical trial with a placebo lead-in phase evaluated the effects of NR (2000 mg/day) on NAD+ and changes in cognitive and long-COVID symptoms.

METHODS: This was a 24-week, double-blind, placebo-controlled trial at a single center in Boston, USA, between August 2021 and September 2023. 58 community-dwelling participants with long-COVID were randomized 2:1 to the NR-NR group (NR for 20 weeks) or the PBO-NR group (PBO for 10 weeks, followed by NR for 10 weeks). The primary outcome was cognition, assessed using the Everyday Cognition scale (ECog), Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), and Trail Making Test-B (TMT-B). Secondary outcomes included the Fatigue Severity Scale (FSS), Beck Depression Inventory (BDI), Beck Anxiety Inventory (BAI), and Pittsburgh Sleep Quality Index. We conducted a mixed model for repeated measures to compare groups, then post-hoc and unadjusted for multiplicity, combined both groups to explore changes from baseline after 10 weeks of NR. This trial was registered with ClinicalTrials.gov (NCT04809974) in 2021.

FINDINGS: 37 participants (64%) were assigned to NR-NR, and 21 participants (36%) to PBO-NR. There was a 32.4% and 51.4% dropout in the NR-NR group at 10 weeks and 20 weeks, respectively, vs. 14.3% dropout at each timepoint in the PBO-NR group. In the NR-NR group, NAD+ levels increased by 2.6- to 3.1-fold after 5-10 weeks of supplementation, respectively, and remained elevated at 20 weeks. In the PBO-NR group, NAD+ levels remained close to baseline (0.93- to 1.0-fold change, 95% CI: 0.5-1.4) during the initial 5 and 10 weeks of PBO. After switching to NR, levels rose to a 2.6-fold and 2.1-fold increase after 5 and 10 weeks of NR, respectively. No significant between-group differences were observed for cognitive outcomes (ECog, RBANS, TMT-B; p-values = 0.47-0.74). There were no significant differences in fatigue severity (p = 0.59), sleep quality p = 0.69), and symptoms of anxiety (p = 0.84) or depression (p = 0.20) between PBO and NR groups. In post-hoc exploratory analysis, examining within-group changes during 5 and 10 weeks of NR intake by grouping all participants during the first 10 weeks of the NR phase, there were significant differences from baseline after 10 weeks of NR in executive functioning, fatigue severity, sleep quality, and symptoms of depression (compared with no significant changes in TMT-B, FSS, PSQI, BAI, or BDI scores during the PBO phase). One serious adverse event was reported, deemed unrelated to the study drug or trial.

INTERPRETATION: In long-COVID, NR increased NAD+ within 5 weeks but did not significantly improve cognition, fatigue, sleep, or mood vs. PBO. Exploratory analyses suggested within-group benefits after 10 weeks of NR, supporting the need for larger trials.

FUNDING: This work was supported by Niagen Bioscience, the MGH McCance Center for Brain Health, Lavine Brain Health Innovation Fund, MGH ECOR CDI Physician-Scientist Development Award, and the Alzheimer's Association (grant no. AARGD-23-114103).},
}

@article {pmid41357309,
year = {2025},
author = {Valdevila Figueira, JA and Ramírez, A and Yambay-Bautista, XR and Carvajal Parra, ID and Valdevila Santiestevan, R and Altamirano Cárdenas, LF and Pico Cucalón, MJ and Rodas, JA},
title = {Psychometric evaluation of the Alzheimer's Disease Knowledge Scale in Ecuadorian university students.},
journal = {Journal of Alzheimer's disease reports},
volume = {9},
number = {},
pages = {25424823251386276},
pmid = {41357309},
issn = {2542-4823},
abstract = {BACKGROUND: Alzheimer's disease (AD) is the leading cause of dementia worldwide, with rising prevalence, high costs, and significant impact in Ecuador. Awareness and validated tools like the Alzheimer's Disease Knowledge Scale (ADKS) are crucial to improve training and early care.

OBJECTIVE: To evaluate the reliability and factorial structure of the ADKS in Ecuadorian university students enrolled in health science programs.

METHODS: A total of 1089 students completed the ADKS. Internal consistency was assessed using Cronbach's alpha and McDonald's omega coefficients. Confirmatory factor analysis (CFA) was conducted using a Diagonally Weighted Least Squares (DWLS) estimator to evaluate the scale's structure.

RESULTS: The ADKS demonstrated acceptable internal consistency (α = 0.767, ω = 0.770). CFA supported the original one-factor model with strong fit indices (RMSEA = 0.047, SRMR = 0.012, CFI = 0.987, TLI = 0.973, RNI = 0.987, NFI = 0.986, RFI = 0.972, IFI = 0.987). These results confirm the scale's internal validity in this population.

CONCLUSIONS: The ADKS is a reliable and valid instrument for assessing knowledge of Alzheimer's disease among Ecuadorian university students. Its use is recommended for both clinical training and public health education strategies focused on dementia awareness.},
}

@article {pmid41357230,
year = {2025},
author = {Xu Lou, I and Zhou, H and Wan, H},
title = {The critical role of Th17 cells and IL-17A in autoimmune and inflammation-associated neurological diseases: mechanisms and therapeutic perspectives.},
journal = {Frontiers in immunology},
volume = {16},
number = {},
pages = {1656422},
pmid = {41357230},
issn = {1664-3224},
mesh = {Humans ; *Th17 Cells/immunology/metabolism ; *Interleukin-17/immunology/metabolism ; Animals ; Inflammation/immunology ; *Autoimmune Diseases/immunology/therapy ; *Nervous System Diseases/immunology/therapy/etiology/metabolism ; *Neuroinflammatory Diseases/immunology/therapy ; },
abstract = {Helper T cells 17 (Th17) and their effector cytokine, interleukin-17A (IL-17A), play a dual role in immune homeostasis. On one hand, they are essential in defense against extracellular pathogens, such as bacteria and fungi, by inducing chemokine production and recruiting neutrophils. On the other hand, their dysregulated activity is strongly linked to autoimmune and inflammatory disorders, including multiple sclerosis, Alzheimer's disease, Parkinson's disease, and others. This article reviews the molecular mechanisms regulating Th17 differentiation and function, emphasizing the role of transcription factors like RORγt and RORα, as well as the influence of cytokines such as IL-6, IL-23, and TGF-β. Additionally, it explores the imbalance between pro-inflammatory Th17 cells and regulatory T cells (Tregs), a critical axis in the pathogenesis of autoimmune and neuroinflammatory diseases. In the context of neurological disorders, Th17 cells can infiltrate the central nervous system (CNS), where they contribute to neuroinflammation by activating microglia and astrocytes, exacerbating damage in conditions such as multiple sclerosis, traumatic brain injury, and neurodegenerative diseases. Emerging therapies, including anti-IL-17 monoclonal antibodies and natural modulators, are discussed as potential strategies to restore the Th17/Treg balance without compromising protective immunity. Finally, the need for further research is highlighted to elucidate the specific mechanisms of Th17 infiltration into the CNS, their interaction with the gut microbiota, and the development of personalized therapies. The integration of immunological, metabolic, and environmental approaches offers promising perspectives for the treatment of Th17/IL-17-mediated diseases.},
}

Humans
*Th17 Cells/immunology/metabolism
*Interleukin-17/immunology/metabolism
Animals
Inflammation/immunology
*Autoimmune Diseases/immunology/therapy
*Nervous System Diseases/immunology/therapy/etiology/metabolism
*Neuroinflammatory Diseases/immunology/therapy

@article {pmid41357227,
year = {2025},
author = {Xie, X and Li, F and Wu, Q and Zeng, C and Chen, X and Wang, W and Zhang, C and Chen, H},
title = {Imbalance of T cell subsets: a core event that mediates the progression of T2DM and its complications.},
journal = {Frontiers in immunology},
volume = {16},
number = {},
pages = {1688392},
pmid = {41357227},
issn = {1664-3224},
mesh = {Humans ; *Diabetes Mellitus, Type 2/immunology/complications/therapy/metabolism/pathology ; Animals ; Disease Progression ; *T-Lymphocyte Subsets/immunology/metabolism ; *Diabetes Complications/immunology/etiology ; Macrophages/immunology ; },
abstract = {Type 2 diabetes mellitus poses a substantial global health burden, increasing evidence highlights the critical role of T cells in promoting T2DM progression. This review provides an overview of the mechanisms by which specific T cell subsets drive T2DM pathogenesis and its complications, while also highlighting emerging immunotherapeutic strategies. Preceding overt T2DM, T cells infiltrate insulin-sensitive tissues early, and a skewing of T cell subsets toward pro-inflammatory phenotypes leads to an imbalance that fosters inflammation and M1 macrophage polarization, driving the development of T2DM. In addition, this T cell subset imbalance contributes to disease progression by inducing insulin resistance and β-cell dysfunction. As T2DM progresses, the T cell subset imbalance and their tissue infiltration extend to the cardiovascular system, kidneys, retina, brain, and peripheral tissues-contributing to diabetic complications such as atherosclerosis, diabetic kidney disease, diabetic retinopathy, Alzheimer's disease, and diabetic foot ulcers. The evidence summarized in this review underscores the central role of T cell subset imbalance in the progression of T2DM and its associated complications. Building on these findings, we also examine both established and emerging therapeutic strategies, including restoring T cell subset balance, modulating T cell-derived pro- and anti-inflammatory cytokines, and shifting macrophage polarization driven by pro-inflammatory T cells, to offer critical insights for future clinical intervention. T cell subset imbalance is a core driver of the progression of T2DM and its complications, and targeting T cell dysregulation represents a promising frontier in T2DM therapy.},
}

Humans
*Diabetes Mellitus, Type 2/immunology/complications/therapy/metabolism/pathology
Animals
Disease Progression
*T-Lymphocyte Subsets/immunology/metabolism
*Diabetes Complications/immunology/etiology
Macrophages/immunology

@article {pmid41357216,
year = {2025},
author = {Liang, E and Wang, W and Zhang, L},
title = {Decoding tRNA dynamics in neuroimmune disorders: mechanistic insights, diagnostic innovations, and therapeutic opportunities.},
journal = {Frontiers in immunology},
volume = {16},
number = {},
pages = {1642370},
pmid = {41357216},
issn = {1664-3224},
mesh = {Humans ; *RNA, Transfer/genetics/metabolism/immunology ; Animals ; Biomarkers ; *Nervous System Diseases/diagnosis/therapy/immunology/genetics ; },
abstract = {Transfer RNA (tRNA) and its derivatives, once regarded solely as translational adaptors, are now recognized as pivotal regulators of neuroimmune homeostasis. Dysregulated tRNA biogenesis, stress-induced fragmentation, and chemical modifications are increasingly implicated in the pathogenesis of neuroinflammatory and neurodegenerative disorders, including multiple sclerosis, neuromyelitis optica spectrum disorder, Alzheimer's disease, and Parkinson's disease. This review synthesizes emerging evidence on tRNA-derived small RNAs (tsRNAs), tRNA-modifying enzymes, and mitochondrial tRNA variants as drivers of immune dysregulation, glial activation, and neuronal injury. We highlight innovative diagnostic biomarkers (e.g., plasma tsRNAs, aminoacyl-tRNA synthetase-interacting multifunctional protein 1) and therapeutic strategies targeting tRNA modification pathways (e.g., queuine analogs, tRNA ligase inhibitors). By bridging tRNA biology with neuroimmunology, this work underscores the translational potential of tRNA-centric approaches in managing complex neurological diseases.},
}

Humans
*RNA, Transfer/genetics/metabolism/immunology
Animals
Biomarkers
*Nervous System Diseases/diagnosis/therapy/immunology/genetics

@article {pmid41357129,
year = {2025},
author = {Rananaware, P and Singh, S and Brahmkhatri, VP},
title = {Scavenging of reactive oxygen and nitrogen species using nanoparticles and their applications in disease management.},
journal = {RSC advances},
volume = {15},
number = {56},
pages = {47955-47980},
pmid = {41357129},
issn = {2046-2069},
abstract = {Nanomaterials constitute a new trend of disease management that is associated with advanced nanotechnology and bioengineered materials, presenting new solutions for various diseases that were previously problematic to handle with traditional chemical drugs or natural materials. Due to their high surface area, charge, variable size, and other properties, nanomaterials have been broadly used to manage several diseases. Specifically, nanomaterials have appeared with a significant ability to act as RONS scavengers for treatment and disease management. This is a result of their versatility in various applications, controlled release, enhanced reactivity, and unique biochemical properties. Recently, specific nanomaterials for treatment and disease management have been effectively developed into clinical tests. This review article focuses on the different types of nanomaterials that are effective for RONS scavenging and are used for different biomedical applications associated with excessive RONS generation. Nanoparticle-based systems have gained significant attention in recent years for their potential applications in scavenging reactive oxygen and nitrogen species (RONS) as part of disease management strategies. These nanoparticles can be designed to enhance the delivery, stability, and efficacy of antioxidants or other scavenging agents. The current review article provides a complete overview of the anti-inflammatory nature and use of nanoparticle systems by examining the molecular and pathological mechanisms of oxidative stress and the function of this stress in both cell and tissue damage. However, it is important to consider the biocompatibility, stability, and potential toxicity of these nanoparticle systems for therapeutic applications. Additionally, targeted delivery and controlled release mechanisms can enhance their efficacy in scavenging RONS at specific disease sites. RONS play a dual role in biological systems-they are essential for various physiological processes, such as cell signalling and host defence, but their overproduction can lead to oxidative and nitrosative stress, contributing to the development and progression of several diseases. Managing RONS is a key aspect of disease prevention and treatment. This article focuses on the use of nanomaterials for the treatment of various cancers, and in other areas such as tissue engineering, wound healing, osteoclast genesis, inflammation, and neurodegenerative disorders, such as Parkinson's and Alzheimer's disease, through RONS scavenging.},
}

@article {pmid41356945,
year = {2025},
author = {Kumar, P and Bhat, A and Goel, D and Mittal, M},
title = {Clinico-Etiological Profile of Young-Onset Dementia From a Tertiary Care Center in Northern India.},
journal = {Cureus},
volume = {17},
number = {11},
pages = {e96203},
pmid = {41356945},
issn = {2168-8184},
abstract = {BACKGROUND: This study examines young-onset dementia (YOD). Young-onset dementia refers to cases of dementia that manifest earlier in life and often pose unique clinical and management challenges. Despite its significant impact, data on YOD in northern India remain limited.

OBJECTIVE: To evaluate the clinico-etiological profile and cognitive characteristics of young-onset dementia patients presenting to a tertiary care center in Uttarakhand, India.

METHODS: This is a longitudinal follow-up study that was conducted over 1.5 years in the Department of Neurology. A total of 37 patients under 65 years of age out of 40 selected, diagnosed with major neurocognitive disorder (DSM-5), were included. Comprehensive clinical assessments, brain imaging, and cognitive evaluations were conducted. Data were analyzed using IBM Corp. Released 2018. IBM SPSS Statistics for Windows, Version 24. Armonk, NY: IBM Corp., with chi-square tests, analysis of variance (ANOVA), and Bonferroni corrections, with significance set at p<0.05.

RESULTS: The majority of patients were males (65%) and aged 56 to 65 years (50%). Vascular dementia was the most common cause (37.8%), followed by Alzheimer's disease (18.9%) and frontotemporal dementia (13.5%). Based on the verbal-language/orientation-memory (VLOM) ratio, 27.5% had frontotemporal-type dementia and 7.5% had Alzheimer-type dementia. Significant cognitive decline (p < 0.05) in MMSE and ACE-III scores was observed in Alzheimer's disease and frontotemporal dementia. Vitamin B12 deficiency showed 13.5% improvement with treatment. VLOM ratios effectively differentiated frontotemporal dementia (FTD) from AD.

CONCLUSION: This study concluded that vascular dementia is the leading cause of YOD in this region, reflecting a high burden of modifiable vascular risk factors. The VLOM ratio offers diagnostic value in distinguishing dementia subtypes. Early identification and intervention are essential to address the functional burden of YOD.},
}

@article {pmid41356880,
year = {2025},
author = {Jamnekar, PP and Dehankar, TJ and Bedre, RV and Dharan, BG and Agravat, B and Agravat, H},
title = {Ashwagandha as an Adaptogenic Herb: A Comprehensive Review of Immunological and Neurological Effects.},
journal = {Cureus},
volume = {17},
number = {11},
pages = {e96183},
pmid = {41356880},
issn = {2168-8184},
abstract = {Ashwagandha (Withania somnifera), a well-established herb in Ayurvedic medicine, is increasingly researched for its adaptogenic properties and regulatory roles in neuroimmune processes. The present review aims to integrate mechanistic, preclinical, and clinical evidence on ashwagandha's immunomodulatory, neuroprotective, psychiatric, sleep-regulating, and anti-inflammatory activities, with emphasis on its bioactive compounds, such as withanolides, sitoindosides, and alkaloids. Such compounds modulate the hypothalamic-pituitary-adrenal (HPA) axis, inhibit NF-κB, induce Nrf2 activation, and affect gamma-aminobutyric acid (GABA)ergic signaling, collectively contributing to its anti-inflammatory, antioxidant, and anxiolytic actions. Clinical trials with standardized ashwagandha extracts have shown reductions in stress-related biomarkers, along with improvements in cognitive performance, sleep quality, and mood parameters. Neuroprotective actions have also been demonstrated in preclinical animal and cell models of Alzheimer's and Parkinson's disease (PD). The review does emphasize methodological shortcomings, however, such as heterogeneity in the preparation of extracts, small sample sizes, variability in endpoints, and possible funding-related biases. To further its clinical utility, subsequent studies should emphasize pharmacogenomic responsiveness given potential variability in cytochrome P450 (CYP)-mediated metabolism and genetic differences in stress-response pathways, along with standardized extract formulations and long-term, multicenter randomized trials with biomarker monitoring. By doing so, ashwagandha promises to be a science-validated botanical that can bridge conventional medicine with precision-guided, evidence-based therapeutic protocols in contemporary medicine.},
}

@article {pmid41356836,
year = {2025},
author = {Liu, X and Zhou, Y and Meng, R and Han, J and Chen, M and Bo, X and Li, S and Song, D and Zhang, Y},
title = {Screening for dual-target enzyme inhibitors derived from Gardenia jasminoides roots, a medicinal and edible plant: investigation of their potential anti-dementia activity.},
journal = {Frontiers in nutrition},
volume = {12},
number = {},
pages = {1682948},
pmid = {41356836},
issn = {2296-861X},
abstract = {INTRODUCTION: Gardenia jasminoides root (GJR) is a traditional Chinese plant valued for its dual functions as both a medicinal herb and an edible resource. Alzheimer's disease (AD) is an irreversible, fatal neurodegenerative disorder in the elderly, and current treatments mainly rely on single-target acetylcholinesterase (AChE) inhibitors with limited effects on disease progression. Thus, there is an urgent need to develop dual-target inhibitors that regulate inflammation (via 5-lipoxygenase, 5-LOX) and improve cholinergic dysfunction (via AChE).

METHODS: To efficiently and accurately screen active compounds, receptor-ligand affinity ultrafiltration coupled with enzyme kinetics was used for rapid identification and characterization. Biochemical assays validated the inhibitory activities and mechanisms of the compounds, while molecular docking and molecular dynamics simulations evaluated target binding affinity and stability at the atomic level. An offline two-dimensional chromatographic method was developed to overcome the limitations of conventional countercurrent chromatography, enhancing peak capacity, and separation efficiency.

RESULTS: Seven active compounds were successfully isolated and identified from GJR, including Shanziside, Deacetylasperulosidic acid methyl ester, Gardoside, Shanzhiside methyl ester, Mussaenoside acid, Eleutheroside E, and 5-Hydroxy-3',4'-dimethoxyflavone. These compounds exhibit potential dual-target inhibitory effects on 5-LOX and AChE, laying the foundation for anti-AD research.

DISCUSSION: This study integrates advanced screening, optimized extraction, and rigorous bioactivity assessment to elucidate the active components of GJR and their anti-AD potential. The developed methodology addresses the shortcomings of single-target drug development and provides valuable insights for the development of dual-target inhibitors and the advancement of plant-based food preparation technologies.},
}

@article {pmid41356819,
year = {2025},
author = {Zhao, Z and Geng, W and Gao, Y and Liu, Y and Nie, S and Yin, Q},
title = {Effects of intermittent fasting on brain health via the gut-brain axis.},
journal = {Frontiers in nutrition},
volume = {12},
number = {},
pages = {1696733},
pmid = {41356819},
issn = {2296-861X},
abstract = {Intermittent fasting (IF), an emerging dietary strategy alternating fasting and feeding cycles, exerts multi-modal brain protection through the regulation of the gut-brain axis. With neurological and mental disorders ranking among the top global disease burdens, IF opens new frontiers in nutritional neuroscience by modulating gut microbiota composition and metabolic pathways, offering a non-pharmacological intervention strategy. Preclinical studies reveal that IF enriches probiotics, reduces neuroinflammation, and restores intestinal barrier integrity, thereby mitigating "leaky gut"-induced cognitive decline. Similarly, the ketogenic effect of IF can improve mitochondrial efficiency, while its anti-inflammatory effect alleviates the pathological changes of multiple sclerosis by suppressing autoreactive T cells. Clinical evidence reveals that IF significantly correlates with decreased β-amyloid burden in Alzheimer's disease (AD) transgenic models and enhanced motor performance in Parkinson's disease (PD) patients, suggesting its multimodal neuroprotective effects. Mental health benefits are equally striking: IF rebalances the Firmicutes-to-Bacteroidetes ratio, which has been linked to anxiety and depression remission. The gut-brain axis (GBA) emerged as a pivotal mediator, with short-chain fatty acids (SCFAs) and tryptophan derivatives fostering serotonin synthesis and oxidative stress reduction. This review synthesizes preclinical and clinical evidence demonstrating how intermittent fasting modulates the gut-microbiota-metabolite-brain axis to promote neuroprotection and mental health benefits, while identifying personalized protocol optimization as a critical avenue for future research.},
}

@article {pmid41356688,
year = {2025},
author = {Hu, L and Chen, Y and Chen, L and Ye, X and Wang, Y and Huang, L and Wang, Y and Zhu, X and Chen, S},
title = {Network analysis of cognition and function in Alzheimer's disease: a cross-sectional study.},
journal = {Frontiers in psychiatry},
volume = {16},
number = {},
pages = {1661313},
pmid = {41356688},
issn = {1664-0640},
abstract = {OBJECTIVES: Traditional approaches in Alzheimer's disease (AD) research examine cognitive symptoms in isolation, potentially overlooking dynamic interrelationships among impairment domains. This study employed network analysis to examine structural organization of cognitive and functional domains in mild (mAD) and moderate-to-severe (Mod-sAD) Alzheimer's disease, aiming to identify stage-specific symptom structures and inform targeted interventions.

METHODS: A cross-sectional study included 134 participants diagnosed with AD according to DSM-5 criteria. Participants were classified into mAD (n=37) and Mod-sAD (n=97) groups. Regularized partial correlation networks with extended Bayesian information criterion regularization examined symptom interdependencies across six CDR domains: memory, orientation, judgment and problem solving, community affairs, home and hobbies, and personal care. Network comparison tests and centrality analyses identified structural differences between disease stages.

RESULTS: The Mod-sAD group demonstrated significantly higher impairment scores across all domains (p < 0.001) with large effect sizes (Cohen's d: 1.83-2.71). Network analysis revealed increased global strength in Mod-sAD versus mAD networks (2.60 vs. 2.49, p < 0.05), indicating greater symptom interconnectedness in advanced stages. Centrality analyses revealed fundamental reorganization: memory emerged as most central in Mod-sAD (strength = 1.62), while judgment and problem-solving showed highest centrality in mAD (strength = 1.65). Orientation centrality increased substantially across progression (strength: -1.32 to 0.40).

CONCLUSIONS: AD progression features increasing network density and centrality shifts from executive-function-centered networks in mild AD to memory-centered networks in moderate-to-severe stages. Findings suggest stage-specific interventions: executive enhancement in mild AD and memory-focused approaches in advanced stages.},
}

@article {pmid41356564,
year = {2025},
author = {Oh, KM and Hong, SR and Beran, K and Song, Y and Lee, JA},
title = {Digital Health Literacy and Self-Efficacy in Using Digital Health Resources Among Caregivers of Individuals with Alzheimer's Disease and Related Dementias.},
journal = {Sage open aging},
volume = {11},
number = {},
pages = {30495334251398089},
pmid = {41356564},
issn = {3049-5334},
abstract = {This study explored digital health literacy skills, self-efficacy in utilizing digital health resources, and self-efficacy in managing personal health among caregivers of individuals with Alzheimer's disease and related dementias (ADRD). Data from the Health Information National Trends Survey 2022 were analyzed, involving a sample of 96 family and unpaid caregivers of individuals with ADRD. Among these caregivers, almost half (49.9%) lacked confidence in using digital health resources. While over 70% used digital health tools like accessing medical information and viewing test results, fewer used health apps (57%) and wearables (48%). Sharing health infomation (21%) and connecting with others with similar health issues (33%) on social media were low, but watching health videos (72%) was popular. Telehealth (59%) and patient portal use (87% for self, 34% for care recipient) were moderate. These findings can inform the development of tailored digital health interventions to provide enhanced support for caregivers in their crucial role.},
}

@article {pmid41356558,
year = {2025},
author = {Wang, H and Yang, F and Gao, Z and Cheng, Z and Liang, X},
title = {The gut-brain axis in Alzheimer's disease: how gut microbiota modulate microglial function.},
journal = {Frontiers in aging},
volume = {6},
number = {},
pages = {1704047},
pmid = {41356558},
issn = {2673-6217},
abstract = {Alzheimer's disease (AD) is a complex neurodegenerative disorder that can be caused by multiple factors, such as abnormal amyloid-beta (Aβ) deposition, pathological changes in Tau protein, lipid metabolism disorders, and oxidative stress. Recent studies have revealed the potential link between gut microbiota and AD, particularly the impact of gut microbiota and its derivatives on microglia. As immune cells in the central nervous system (CNS), microglia are involved in neuroinflammation and the regulation of cognitive function. Research indicates that the dysregulation of gut microbiota may affect the phenotype and function of microglia through various mechanisms, including direct metabolite action and indirect immune and neurotransmitter regulation. This article reviews the direct and indirect effects of gut microbiota and its derivatives on microglia, explores their role in the pathogenesis of AD, and discusses therapeutic strategies based on gut microbiota, such as dietary regulation, probiotics, fecal microbiota transplantation, and traditional Chinese medicine. Although existing studies have shown the potential of these interventions, further research is needed to completely understand their application in the treatment of AD.},
}

@article {pmid41356340,
year = {2025},
author = {Solomon, ED and Gabel, M and Bekena, S and Goswami, S and Moulder, KL and Morris, JC and Mozersky, J},
title = {Study partners' views on remuneration in longitudinal Alzheimer's disease research.},
journal = {Alzheimer's & dementia. Behavior & socioeconomics of aging},
volume = {1},
number = {4},
pages = {},
pmid = {41356340},
issn = {2997-3805},
abstract = {INTRODUCTION: Recruiting and retaining participants in Alzheimer's disease (AD) research poses a consistent challenge. Remuneration is one "readily modifiable factor" that could improve recruitment and retention in longitudinal observational AD research, and guidance suggests that all participants and their study partners receive remuneration for participating in AD longitudinal research.

METHODS: We surveyed study partners (N = 517) at one Alzheimer's Disease Research Center in the United States regarding their views on remuneration.

RESULTS: Study partners felt largely neutral to positive regarding remuneration. Self-identified Black study partners had more positive views on remuneration than White study partners. Study partners with the least favorable views on remuneration perceived a lower participation burden and were less motivated by the perceived personal benefits of participating. All study partners were motivated by altruism and committed to continued participation.

DISCUSSION: Most study partners perceive remuneration as acceptable. Remuneration may improve recruitment and retention of historically underrepresented groups.},
}

@article {pmid41356329,
year = {2025},
author = {Boer, D and Winkler, B and Schmidt, C and Sterke, S and Achterberg, W and Vlieland, TV},
title = {A 10-week physical therapist-supervised exercise program for nursing home residents with dementia: a single arm, observational feasibility study.},
journal = {JAR life},
volume = {14},
number = {},
pages = {100043},
pmid = {41356329},
issn = {2534-773X},
abstract = {BACKGROUND: Evidence on the effectiveness of exercise interventions for nursing home residence with dementia is scarce, with considerable practice variation with respect to their contents and dosage. This study aimed to evaluate the feasibility of an adequately dosed, personalized exercise intervention with respect to the assessment instruments, participants' adherence and the occurrence of serious adverse events (primary feasibility outcomes) as well as the participant recruitment and participants' and supervisors' perceptions and experiences (secondary feasibility outcomes).

DESIGN: Single-arm observational study.

SETTING: Two nursing homes in Haarlem, the Netherlands.

PARTICIPANTS: Nursing home residents with a confirmed diagnosis of dementia who were able to walk 50 meters (with or without walking aid), without expected resistance to the intervention.

INTERVENTION: 10-week program, with two group-based sessions including strength and balance exercises, and two individual exergaming cycling sessions per week. The sessions were tailored to the participant via standardized assessments and supervised by a physical therapist.

RESULTS: Of 59 residents screened, 11 enrolled. Four of six clinical assessments were completed by all, and two by nine and ten participants, respectively. Nine participants completed both components, one only the individual exergaming part, and one participant dropped out. Adherence rates were 92 % for the group and 87 % for the individual sessions. Among 137 reported adverse events, nine were possibly related to the intervention, all minor and transient. The median participant appraisal score was 4.3 (out of five). Supervisors highlighted dementia-specific knowledge, individualized communication, and tailored approaches as facilitators, while scheduling conflicts posed challenges.

CONCLUSION: A 10-week, personalized, physical therapist-led exercise program for nursing home residents with dementia is feasible, with high adherence and positive evaluations. A pilot study to refine the recruitment and intervention procedures as well as pre-and post-intervention outcome measurements is needed prior to scaling up to a larger clinical trial assessing effectiveness.},
}

@article {pmid41356255,
year = {2025},
author = {Vahid, A and Zamani, J and Hadi Hosseini, SM},
title = {Predicting future amyloid conversion: the role of baseline amyloid distribution, genetic and cognitive resilience.},
journal = {NPJ dementia},
volume = {1},
number = {1},
pages = {40},
pmid = {41356255},
issn = {3005-1940},
abstract = {Alzheimer's disease (AD) is characterized by early accumulation of amyloid beta (Aβ) prior to cognitive decline. Although Aβ plays a normal role in brain function, excessive buildup is a key early indicator of AD. The transition from Aβ-negative to Aβ-positive reflects disease progression, but patterns predicting this shift remain unclear. Using longitudinal Aβ PET imaging data from the Alzheimer's Disease Neuroimaging Initiative (ADNI), we developed a survival-based machine learning model to estimate the timing of Aβ conversion. The model showed strong predictive accuracy (concordance index = 0.845). SHAP analysis identified higher baseline Aβ burden in frontoparietal and striatal regions, particularly the rostral and caudal middle frontal cortex, as predictors of faster conversion. APOE4 homozygosity and lower baseline cognitive performance were also associated with earlier Aβ positivity. Kaplan-Meier analysis estimated a median transition time of 4.06 years. These findings support machine learning for early AD risk prediction and timely intervention planning.},
}

@article {pmid41356006,
year = {2025},
author = {Gandhi, A and Parhizgar, A},
title = {GLP-1 receptor agonists in Alzheimer's and Parkinson's disease: endocrine pathways, clinical evidence, and future directions.},
journal = {Frontiers in endocrinology},
volume = {16},
number = {},
pages = {1708565},
pmid = {41356006},
issn = {1664-2392},
mesh = {Humans ; *Alzheimer Disease/drug therapy/metabolism ; *Parkinson Disease/drug therapy/metabolism ; *Glucagon-Like Peptide-1 Receptor Agonists ; Animals ; Signal Transduction/drug effects ; },
abstract = {Initially developed for type 2 diabetes and obesity, glucagon-like peptide-1 receptor agonists (GLP-1RAs) are now emerging as promising candidates for modifying the course of neurodegenerative diseases. This potential stems from the presence of GLP-1 and its receptors within the central nervous system (CNS), where their signaling activity influences critical processes like synaptic plasticity, neuroinflammation, insulin signaling, and cellular energy management. In fact, preclinical models of both Alzheimer's disease (AD) and Parkinson's disease (PD) have shown that GLP-1RAs can reduce neuroinflammation, improve mitochondrial function, and enhance the clearance of toxic proteins (proteostasis), leading to benefits in cognition and the survival of dopaminergic neurons. Yet, when tested in humans, the picture has been more nuanced and less straightforward. Early clinical trials in AD have produced mixed cognitive signals, though they have shown intriguing biological effects, such as preserved cerebral glucose metabolism with liraglutide on FDG-PET scans. In contrast, the evidence in PD has been more consistent, with agents like exenatide and lixisenatide demonstrating motor benefits, although one trial with a pegylated exendin (NLY01) did not meet its primary endpoint. The definitive test will come from large, ongoing phase 3 programs, such as the EVOKE and EVOKE+ trials for semaglutide. Should these trials are successful, GLP-1RAs could become a cornerstone of earlier, mechanism-based intervention strategies for neurodegenerative diseases.},
}

Humans
*Alzheimer Disease/drug therapy/metabolism
*Parkinson Disease/drug therapy/metabolism
*Glucagon-Like Peptide-1 Receptor Agonists
Animals
Signal Transduction/drug effects

@article {pmid41355893,
year = {2025},
author = {},
title = {Correction to "Plasma lipid metabolites as biomarkers of early white matter degeneration in Alzheimer's disease".},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {17},
number = {4},
pages = {e70234},
doi = {10.1002/dad2.70234},
pmid = {41355893},
issn = {2352-8729},
abstract = {[This corrects the article DOI: 10.1002/dad2.70217.].},
}

@article {pmid41355756,
year = {2025},
author = {Liu, F and Tang, YL and Zhang, ZB and Tan, YH and Lin, SH and Wang, NY and Li, JN and Pan, ZJ and Li, JF and Huang, JF and Ding, YQ and Guo, CM and Xu, L and Peng, C and Zhou, QX},
title = {Modifying Glucose Metabolism Reverses Memory Defects of Alzheimer's Disease Model at Late Stages.},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
volume = {},
number = {},
pages = {e06695},
doi = {10.1002/advs.202506695},
pmid = {41355756},
issn = {2198-3844},
support = {2022ZD0204900//National Program of Brain Science and Brain-Inspired Intelligence Technology 2030/ ; 32271080//National Natural Science Foundation of China/ ; 32071029//National Natural Science Foundation of China/ ; 82473909//National Natural Science Foundation of China/ ; 32170662//National Natural Science Foundation of China/ ; 32070818//National Natural Science Foundation of China/ ; 202401AS070131//Yunnan Fundamental Research Project/ ; 202402AA310014//Yunnan Provincial Science and Technology Department/ ; LG-QS-202205-05//The Lingang Laboratory/ ; 202001BB050005//Natural Science Foundation of Yunnan Province/ ; //Xingdian talent program of Yunnan Province/ ; },
abstract = {Significant efforts have harvested a sophisticated understanding of Alzheimer's disease (AD) including amyloid beta (Aβ) cascade mechanisms, although effective treatment for reversing or stopping AD progression is not available. This study reports that ferul enanthate (SL), a novel derivative of active agents targeting brain microvessels, oxidative phosphorylation, and ATP generation can reverse the hippocampus-dependent spatial memory defects and reduce Aβ plaques in AD model mice (APP/PS1) at advanced stages. Spatial transcriptomics discovers that SL endows a cluster of genes expressing in Aging-AD-Rescue (AAR) pattern, which is prominent in hippocampal dendritic region where Aβ plaques are densely deposited. Furthermore, this AAR rule covers hippocampal Glut1 (glucose transporter 1) expression and ATP generation, which are further confirmed by immunoblotting or immunofluorescence studies. Our data demonstrate that SL can still reverse memory defects at advanced stages of AD mice by modifying aging-dependent multiple pathologies of AD, particularly promoting Glut1 expression and ATP generation.},
}

@article {pmid41355717,
year = {2025},
author = {Tripathi, S and Singh, R and Jaiswal, S and Sethi, M and Rana, R and Mishra, K and Chourasia, MK},
title = {Targeting Alzheimer's pathophysiology with carbon dots: from mechanisms to therapy.},
journal = {Journal of materials chemistry. B},
volume = {},
number = {},
pages = {},
doi = {10.1039/d5tb02134k},
pmid = {41355717},
issn = {2050-7518},
abstract = {Alzheimer's disease continues to be a debilitating disorder, profoundly affecting the quality of life, despite decades of extensive research. The impermeability of the blood-brain barrier, multifactorial etiology of the disease and the repeated failures of single target therapy are the major contributors of this therapeutic stagnation. If there is a silver lining, it lies in the growing advancement of multi-targeted therapeutic approaches that address the complex pathophysiology of Alzheimer's disease. In this context, carbon dots have emerged as highly promising, ultrasmall and biocompatible nanomaterials capable of traversing the blood-brain barrier and targeting various pathophysiologies of the disease. These include but are not limited to inhibition of abnormal protein aggregation, scavenging of reactive oxygen species and attenuation of neuroinflammatory processes. This review aims to critically synthesize the current body of research on carbon dots with particular emphasis on their mechanistic insights, surface chemistry driven targeting strategies and ligand free transportation mechanisms. The indulgence of photodynamic therapy in targeting carbon dots has also been touched upon. The key regulatory hurdles and translational gaps have been addressed that hinder their journey from bench to bedside. This review highlights the potential of carbon dots as intelligent nanoplatforms by integrating the molecular and pharmacological perspectives.},
}

@article {pmid41355547,
year = {2025},
author = {Lu, Q and Di, X and Guo, X},
title = {Comprehensive Review on the Protective Effects of Lycium barbarum Polysaccharide on Neurodegenerative Diseases.},
journal = {Endocrine, metabolic & immune disorders drug targets},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118715303393082251027072838},
pmid = {41355547},
issn = {2212-3873},
abstract = {Neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, Huntington's disease, ischemic stroke, and other related conditions, significantly impact the quality of life, particularly in low-income nations. The pathogenesis of these diseases is driven by neuroinflammation, oxidative stress, apoptosis, mitochondrial dysfunction, and regulation of autophagy. To date, no therapies or medications can fully reverse the progression of these diseases. Natural polysaccharides have demonstrated significant therapeutic potential in the treatment of neurodegenerative diseases. Lycium barbarum polysaccharide, derived from the traditional Chinese medicine Lycium barbarum L., has attracted considerable attentionfor its diverse biological activities, biodegradability, ease of modification, and low toxicity. This review aims to systematically evaluate the neuroprotective effects of Lycium barbarumpolysaccharides and their mechanisms in various neurodegenerative disease models. For this study, we used multiple scientific databases, including PubMed, Scopus, Web of Science, and Google Scholar. We verified the correct plant name through the website plantlist.org. The search results were interpreted and documented based on the retrieved bibliographic information. Lycium barbarum polysaccharide has shown significant therapeutic potential for the treatment of neurodegenerative diseases. Experimental evidence reveals its neuroprotective effects through various mechanisms, including reducing neuroinflammation, alleviating oxidative stress, inhibiting apoptosis, improving mitochondrial function, and regulating autophagy. The current review established that Lycium barbarum polysaccharide holds promise as a therapeutic agent for neurodegenerative diseases. However, further research is required to address the limitations identified in previous studies and to guide future experimental investigations and clinical applications.},
}

@article {pmid41355503,
year = {2025},
author = {Srivastava, K and Srivastava, R},
title = {Integrative bioinformatics analysis of APOE variants in Alzheimer's disease and clinical therapeutics.},
journal = {Journal of biomolecular structure & dynamics},
volume = {},
number = {},
pages = {1-21},
doi = {10.1080/07391102.2025.2597291},
pmid = {41355503},
issn = {1538-0254},
abstract = {In this study, a comprehensive bioinformatics workflow is employed to investigate the impact of APOE gene variants on Alzheimer's disease (AD) and to explore their relevance for improving therapeutic strategies. Multiple databases were screened to identify key non-synonymous single nucleotide polymorphisms (nsSNPs) in APOE. Six variants: rs769452 (L46P), rs429358 (C130R), rs267606664 (G145D), rs121918393 (R154S), rs7412 (R176C), and rs267606661 (R269G) were selected, of which five were predicted to be deleterious. Given its high interaction score (0.789), the FDA-approved AD drug Donepezil was chosen as the ligand to assess binding with both wild-type and mutant APOE proteins. Structural modeling using AlphaFold3 generated high-quality APOE structures, and in silico mutagenesis revealed mutation-dependent destabilization. AutoDock4 molecular docking was performed to evaluate binding affinities of Donepezil with the predicted active-site residues of wild-type and mutant APOE. Furthermore, 100 ns molecular dynamics simulations using AMBER20 were conducted for all APOE-Donepezil complexes. Analyses of RMSD, RMSF, and radius of gyration indicated overall structural stability, residue-level flexibility, and protein compactness throughout the simulations. Interaction profiling revealed stable hydrophobic contacts and hydrogen bonds in both wild-type and mutant complexes. Our findings suggest that structural variations arising from APOE genotypes may modulate Donepezil binding and potentially influence therapeutic response in AD patients. However, these computational predictions require validation through biophysical assays, cellular experiments, and genotype-stratified clinical studies. Integrating molecular modeling with experimental research will be essential for advancing APOE-guided precision medicine and optimizing Donepezil therapy for Alzheimer's disease.},
}

@article {pmid41355388,
year = {2025},
author = {Alla, D and Malireddi, A and Ramsundar, R and Shah, D and Alla, SSM and Das, A and Andanappa, A and Emmanuel, NW and Siddiqui, S and Marepalli, NR and Dugyala, RR and Kolte, R},
title = {Efficacy and Safety of Gantenerumab in Patients With Alzheimer Disease: A Systematic Review and Meta-analysis.},
journal = {Clinical neuropharmacology},
volume = {},
number = {},
pages = {},
doi = {10.1097/WNF.0000000000000661},
pmid = {41355388},
issn = {1537-162X},
abstract = {BACKGROUND: Alzheimer disease is the most common cause of dementia and a major global health concern with a significant impact on elderly individuals and society. Gantenerumab, a monoclonal antibody that targets aggregated amyloid beta and removes Aβ plaques, could potentially treat Alzheimer disease.

OBJECTIVES: To systematically evaluate the safety of gantenerumab in patients with Alzheimer disease through a meta-analysis of available clinical studies.

MATERIALS AND METHODS: A comprehensive literature search was conducted, and six studies were included. Extracted data included study year, location, sample size, age, gender, gantenerumab dosage, APOE4 status, cognitive scores, CSF biomarkers, PET-SUVr, Changes in mental function, hippocampal volume, PET-SUVr, adverse effects, and mortality. Analysis was done using the R software.

RESULTS: ADAS scores increased less in the gantenerumab group than in the placebo group (MD=-1.25, 95% CI:-1.40 to -1.10, P<0.00001, I²=88%). The increase in the FAQ score was also smaller (MD=-0.82, 95% CI: -0.92 to -0.72, P<0.00001, I²=87%). Hippocampal volumes significantly improved (right: MD=11.93, P=0.01; left: MD=12.24, P=0.008). However, gantenerumab was linked to higher rates of ARIA-E (OR=25.62, P<0.00001) and ARIA-H (OR=1.80, P<0.00001).

CONCLUSION: In conclusion, patients with Alzheimer disease treated with gantenerumab showed significant improvement in the ADAS score, FAQ score, hippocampal volume, and CSF biomarkers compared with those treated with placebo. However, the use of gantenerumab is associated with a higher incidence of ARIA-E and ARIA-H.},
}

@article {pmid41355362,
year = {2025},
author = {Patil, VS and Parekh, B and Sharma, A and Farah, H and Jyothi-S, R and Mishra, S and Nanda, A and Al-Hasnaawei, S and Kumar-Mishra, M},
title = {Therapeutic and Diagnostic Roles of MSC-Derived Exosomes in Alzheimer's Disease.},
journal = {Brain and behavior},
volume = {15},
number = {12},
pages = {e71112},
doi = {10.1002/brb3.71112},
pmid = {41355362},
issn = {2162-3279},
mesh = {*Exosomes/metabolism ; Humans ; *Alzheimer Disease/therapy/diagnosis/metabolism ; *Mesenchymal Stem Cells/metabolism ; Animals ; Blood-Brain Barrier/metabolism ; },
abstract = {PURPOSE: Alzheimer's disease (AD), the leading cause of dementia, is characterized by amyloid-β accumulation, tau hyperphosphorylation, neuroinflammation, and synaptic failure, with no curative therapies available. This review aims to explore innovative therapeutic and diagnostic strategies, focusing on mesenchymal stem cell-derived exosomes (MSC-exos) as potential disease-modifying agents.

METHOD: The review synthesizes current evidence on the regenerative, immunomodulatory, and neuroprotective properties of mesenchymal stem cells (MSCs) and their exosomes. It examines how MSC-exos, as nanosized extracellular vesicles carrying proteins, lipids, and nucleic acids, interact with the central nervous system to modulate disease pathways.

FINDINGS: MSC-exos can cross the blood-brain barrier (BBB), deliver neurotrophic factors, modulate microglial activity, enhance amyloid clearance, and support neuronal survival and synaptic plasticity. They also hold promise as biomarkers by reflecting central nervous system pathology in peripheral biofluids. Early clinical trials using MSCs from bone marrow, adipose tissue, and umbilical cord show safety and feasibility, with exosome-based approaches offering scalable, cell-free alternatives.

CONCLUSION: MSC-derived exosomes present a promising avenue for both therapeutic intervention and early diagnosis in AD, offering neuroprotective, anti-inflammatory, and pro-regenerative effects. However, further progress requires addressing challenges such as exosome isolation standardization, cargo characterization, and regulatory considerations to enable their translation into clinical practice.},
}

*Exosomes/metabolism
Humans
*Alzheimer Disease/therapy/diagnosis/metabolism
*Mesenchymal Stem Cells/metabolism
Animals
Blood-Brain Barrier/metabolism

@article {pmid41355337,
year = {2025},
author = {Anayiti, X and Ding, Y and Li, W and Tan, M and Chen, P and Xie, Z and Tao, M and Xiang, Y and Liu, Y and Xu, X and Wang, P},
title = {Adaptive Frequency-Optimized Wavelet Networks for Early Detection of Subjective Cognitive Decline via Resting-State fMRI.},
journal = {Brain and behavior},
volume = {15},
number = {12},
pages = {e71039},
doi = {10.1002/brb3.71039},
pmid = {41355337},
issn = {2162-3279},
support = {CSTB2025NSCQ-GPX0857//Natural Science Foundation of Chongqing/ ; KJQN202300718//Scientific and the Technological Research Program of Chongqing Municipal Education Commission/ ; 2018ZHYL0105//Shanghai Municipal Health and Family Planning Commission Smart Medical Special Research Project/ ; ITJ(ZD)2301//Project supported by Clinical Research Project of Tongji Hospital of Tongji University/ ; ITJ(QN)2312//Project supported by Clinical Research Project of Tongji Hospital of Tongji University/ ; SHDC2020CR1038B//Clinical Research Plan of SHDC/ ; 2022YFC2009904//National Key Research and Development Program of China/ ; 2022YFC2009900//National Key Research and Development Program of China/ ; ITJ(ZD)2301//Research Project of Shanghai Municipal Health Commission/ ; ITJ(QN)2312//Research Project of Shanghai Municipal Health Commission/ ; 82102023//National Natural Science Foundation of China/ ; 81830059//National Natural Science Foundation of China/ ; 82227807//National Natural Science Foundation of China/ ; 62306051//National Natural Science Foundation of China/ ; 62481540175//National Natural Science Foundation of China/ ; tsqn202507225//Taishan Scholars Foundation of Shandong Province/ ; },
mesh = {Humans ; *Magnetic Resonance Imaging/methods ; *Cognitive Dysfunction/physiopathology/diagnosis/diagnostic imaging ; Male ; Female ; Aged ; Early Diagnosis ; Middle Aged ; Wavelet Analysis ; *Nerve Net/physiopathology/diagnostic imaging ; Brain/physiopathology/diagnostic imaging ; Alzheimer Disease/physiopathology ; },
abstract = {BACKGROUND: Early detection of subjective cognitive decline (SCD), a preclinical stage of Alzheimer's disease (AD), remains a clinical challenge due to its subtle manifestations. This study aims to address these challenges by introducing a novel approach to enhance the detection and analysis of SCD.

METHODS: A Frequency Self-Adaptive Wavelet Transform (FSAWT) model was developed and optimized for functional brain network (FBN) construction using resting-state functional MRI (rs-fMRI) data. The model dynamically selected "golden frequencies" to improve the accuracy and interpretability of brain connectivity patterns. FBNs from 240 participants (106 SCD, 134 controls) were analyzed and compared using traditional methods, pearson correlation (PC) and sparse representation (SR). Receiver operating characteristic-area under the curve (ROC-AUC) analysis validated the classification results.

RESULTS: Our findings demonstrate that individuals with SCD exhibit distinct functional connectivity alterations, including reversed parahippocampal gyrus-superior parietal gyrus connectivity-suggesting early DMN disintegration, weakened temporoparietal pathways linked to memory deficits, and enhanced fusiform gyrus-orbitofrontal connectivity. The frequency-optimized SRWT method achieved superior diagnostic performance (83.71% accuracy, AUC = 0.84) with 82.11% sensitivity and 85.71% specificity, significantly outperforming traditional approaches (61.93% accuracy for PC), highlighting its potential for early SCD detection through these network-based biomarkers.

CONCLUSIONS: The FSAWT model offers a robust framework for early SCD detection by integrating frequency-specific and cross-frequency dynamics. While these findings highlight potential contributions to precision diagnostics and personalized interventions for neurodegenerative disorders, such applications remain to be established in future studies. Future applications may also explore multimodal neuroimaging and broader cognitive impairments.},
}

Humans
*Magnetic Resonance Imaging/methods
*Cognitive Dysfunction/physiopathology/diagnosis/diagnostic imaging
Male
Female
Aged
Early Diagnosis
Middle Aged
Wavelet Analysis
*Nerve Net/physiopathology/diagnostic imaging
Brain/physiopathology/diagnostic imaging
Alzheimer Disease/physiopathology

@article {pmid41355080,
year = {2025},
author = {van Dyck, CH and Sperling, R and Johnson, K and Dhadda, S and Kanekiyo, M and Li, D and Gee, M and Hersch, S and Irizarry, M and Kramer, L},
title = {Long-term safety and efficacy of lecanemab in early Alzheimer's disease: Results from the clarity AD open-label extension study.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {12},
pages = {e70905},
doi = {10.1002/alz.70905},
pmid = {41355080},
issn = {1552-5279},
support = {//Eisai Inc. and Biogen/ ; },
mesh = {Humans ; *Alzheimer Disease/drug therapy/pathology ; Female ; Male ; Aged ; Quality of Life ; Treatment Outcome ; Disease Progression ; Amyloid beta-Peptides ; Aged, 80 and over ; },
abstract = {INTRODUCTION: In Clarity AD, lecanemab reduced markers of amyloid in early symptomatic Alzheimer's disease and slowed cognitive and functional decline at 18 months. Herein, we report 36-month data from the ongoing open-label extension (OLE).

METHODS: Clarity AD is an 18-month, randomized study (Core), with an OLE where participants received open-label lecanemab. Clinical and health-related quality-of-life (HRQoL) outcomes were evaluated overall and by examining "delayed-start" and "early-start" cohorts. Low pathology (i.e., low baseline amyloid or tau) subgroups were analyzed.

RESULTS: ARIA rates were low after 6 months and not associated with long-term progression. Across clinical and HRQoL endpoints, lecanemab-treated participants continued to benefit through 36 months. Separation between early and delayed start was maintained between 18 and 36 months. The low pathology subgroup showed stability or improvement over 18-36 months.

DISCUSSION: Benefit continued to accrue with ongoing lecanemab treatment through 36 months. Results in the low pathology subgroup support early initiation of lecanemab treatment.

HIGHLIGHTS: This research evaluated the long-term efficacy, safety, and HRQoL results from an ongoing extension of the phase 3 Clarity AD, which included open-label lecanemab treatment for up to 36 months. Overall, the results show participants continue to accrue a lecanemab treatment benefit up to 36 months and highlight the importance of continued long-term lecanemab treatment. Results presented in our paper demonstrate that lecanemab continued suppression of amyloid plaque levels and significantly slowed clinical decline on multiple measures of cognition, function, and quality of life in early AD at 18 months and continued for 36 months to date. No new safety signals were observed with continued lecanemab treatment. After the first 6 months, ARIA rates were low and similar to ARIA rates on placebo, with no association between ARIA occurrence and accelerated long-term clinical progression. Taken together with existing data, these results provide a clear rationale and a demonstration of the disease modification effects of long-term lecanemab therapy.},
}

Humans
*Alzheimer Disease/drug therapy/pathology
Female
Male
Aged
Quality of Life
Treatment Outcome
Disease Progression
Amyloid beta-Peptides
Aged, 80 and over

@article {pmid41355015,
year = {2025},
author = {Ye, R and Pereira, TP and Locascio, JJ and Goodheart, AE and Peterec, EC and Brickhouse, M and Dickerson, BC and Touroutoglou, A and Gomperts, SN},
title = {Regional cortical network atrophy predicts progression to dementia in the Lewy body diseases.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {12},
pages = {e70963},
doi = {10.1002/alz.70963},
pmid = {41355015},
issn = {1552-5279},
support = {1R21 NS109833//National Institute of Neurological Disorders and Stroke (NINDS)/ ; U01 AG016976-11//National Institute of Neurological Disorders and Stroke (NINDS)/ ; NIH P30AG062421//National Institute of Neurological Disorders and Stroke (NINDS)/ ; R01 AG085377/AG/NIA NIH HHS/United States ; R21 AG080588/AG/NIA NIH HHS/United States ; CDMRP/W81XW1810516//U.S. Department of Defense/ ; //Michael J. Fox Foundation for Parkinson's Research/ ; R21 AG080588/AG/NIA NIH HHS/United States ; 1R21 NS109833/NS/NINDS NIH HHS/United States ; },
mesh = {Humans ; *Lewy Body Disease/pathology/diagnostic imaging/complications ; Disease Progression ; Male ; Female ; Aged ; Magnetic Resonance Imaging ; Atrophy/pathology ; Longitudinal Studies ; *Cerebral Cortex/pathology/diagnostic imaging ; Aged, 80 and over ; Neuropsychological Tests ; *Dementia/etiology/pathology/diagnostic imaging ; },
abstract = {INTRODUCTION: The timeline from symptom onset to the loss of independent functioning varies across patients with Lewy body disease (LBD). Here, we investigate whether the magnitude of cortical atrophy within functional networks that subserve cognitive and affective functions has utility in predicting progression to dementia in LBD.

METHODS: Forty-six LBD patients with intact instrumental and basic activities of daily living at baseline underwent brain magnetic resonance imaging scans and longitudinal clinical assessments. Cortical atrophy was estimated in LBD patients relative to an amyloid-negative control group.

RESULTS: Multivariate Cox regression analysis demonstrated that atrophy in the affective salience and limbic networks, but not in cognitive, motor, or visual networks, predicted progression to dementia after controlling for disease duration, diagnosis, amyloid beta status, and baseline cognitive severity.

DISCUSSION: Baseline atrophy in the salience and limbic networks is an important predictor of progression to dementia and may have value in identifying early-stage LBD patients at risk for faster progression.

HIGHLIGHTS: In this longitudinal study of the Massachusetts Alzheimer's Disease Research Center's Memory and Aging Cohort, although the magnitude of cortical atrophy in the early stages of Lewy body disease (LBD) was highly variable at the individual level, atrophy in the salience-limbic network predicted progression to dementia in LBD. In the early stages of LBD, each one standard deviation increase in salience-limbic atrophy doubled the risk of dementia. These findings were robust to adjustment for disease duration, diagnosis, amyloid beta status, and baseline cognitive severity.},
}

Humans
*Lewy Body Disease/pathology/diagnostic imaging/complications
Disease Progression
Male
Female
Aged
Magnetic Resonance Imaging
Atrophy/pathology
Longitudinal Studies
*Cerebral Cortex/pathology/diagnostic imaging
Aged, 80 and over
Neuropsychological Tests
*Dementia/etiology/pathology/diagnostic imaging

@article {pmid41354963,
year = {2025},
author = {Choudhury, A and Yesiltepe, M and Lashley, T and Singh, V and Minhas, V and Yin, T and Fernandez, A and D'Adamio, L and Ahn, HJ},
title = {Pathological mechanisms of motor dysfunction in familial Danish dementia: insights from a knock-in rat model.},
journal = {Journal of neuroinflammation},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12974-025-03537-w},
pmid = {41354963},
issn = {1742-2094},
support = {AG033007/GF/NIH HHS/United States ; NS104386/GF/NIH HHS/United States ; },
abstract = {Familial Danish Dementia (FDD) is a rare autosomal dominant neurodegenerative disorder caused by a mutation in the integral membrane protein 2B (ITM2b) gene. Clinically, FDD is characterized by cerebral amyloid angiopathy (CAA), cerebellar ataxia, and dementia. Notably, FDD shares several neuropathological features with Alzheimer's disease (AD), including CAA, neuroinflammation, and neurofibrillary tangles. In this study, we investigate the pathological mechanisms linking CAA, white matter damage, and motor dysfunction using a recently developed FDD knock-in (FDD-KI) rat model. This model harbors the Danish mutation in the endogenous rat Itm2b gene, along with an App gene encoding humanized amyloid-β (Aβ). Our analysis revealed substantial vascular Danish amyloid (ADan) deposition in the cerebellar subpial and leptomeningeal vessels of FDD-KI rats, showing an age-related increase comparable to that observed in human FDD patients. Additionally, vascular Aβ deposits (Aβ-CAA) were present in FDD-KI rats, but Aβ-CAA patterns showed some differences between species: in FDD patients, Aβ-CAAs were more abundant in subpial large vessels, while in FDD-KI rats, Aβ-CAA was mostly observed in capillaries. Motor function assessments in FDD-KI rats demonstrated age-accelerated motor deficits and gait abnormalities, mirroring the clinical characteristics of FDD patients. To further explore the mechanisms underlying these deficits, we examined cerebellar pathology and found age-related myelin disruption and axonal fiber loss, consistent with postmortem human FDD pathology. Cerebellar demyelination appeared to be driven by neuroinflammation, marked by increased microglial/macrophage activation in response to vascular amyloid deposition. Additionally, we observed extravascular fibrinogen leakage, indicating widespread vascular permeability in both white and gray matter, with fibrinogen deposits surrounding amyloid-positive vessels in aged FDD-KI rats and postmortem FDD cerebellum. These findings suggest that CAA and fibrinogen leakage in FDD may drive neuroinflammation, demyelination, and axonal damage in the cerebellum, potentially contributing to the motor and gait impairments observed in FDD.},
}

@article {pmid41354833,
year = {2025},
author = {M'Bra, PEH and Suárez-Uribe, I and Avino, M and Ng Kwan Lim, E and Mayhue, M and Balthazar, P and Aumont, A and Prévost, K and Massé, E and Fernandes, KJL},
title = {Medium-chain triglycerides and ketogenic diet prevent alterations of the gut microbiome in transgenic Alzheimer's disease mice.},
journal = {Communications biology},
volume = {},
number = {},
pages = {},
doi = {10.1038/s42003-025-09171-9},
pmid = {41354833},
issn = {2399-3642},
abstract = {The systemic mechanisms underlying the benefits of ketogenic interventions on cognition in Alzheimer's disease (AD) are understudied. Interventions involving a carbohydrate-free high-fat ketogenic diet (KD) or dietary supplementation with medium-chain triglycerides (MCT) both improve cognition in AD mouse models, yet with opposing effects on circulating ketones levels, peripheral insulin sensitivity and inflammation. Since the gut microbiome regulates systemic metabolism and inflammation and is altered by aging and disease, we investigated how it is affected in mice subjected to MCT and KD. At early stages of pathology, AD mice exhibited substantially reduced richness and distinct composition of gut microbiome species. Administration of MCT or KD for 1-month increased microbiome diversity, restoring the levels of more than 50% of the bacteria altered in AD mice and inducing novel alterations. Both diets increased levels of short-chain fatty acid-producing bacteria, such as Lachnospiraceae, which directly correlated with improved hippocampal dendritic spine density. Interestingly, longer term administration of KD increased the obesity-associated Firmicutes/Bacteroidota ratio and bodyweight in AD but not WT mice, suggesting that AD-associated metabolic defects should be considered when designing such intervention. We conclude that MCT and KD may influence AD central and peripheral defects in part via modulation of the gut microbiome.},
}

@article {pmid41354755,
year = {2025},
author = {Martí-Navia, A and Álvarez-Sánchez, L and Ferré-González, L and López, A and Peña-Bautista, C and Balaguer, Á and Pedrosa, N and Vico, H and Baquero, M and Cháfer-Pericás, C},
title = {Clinical validation of new alzheimer disease diagnosis tools based on plasma p-Tau217.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-025-31613-x},
pmid = {41354755},
issn = {2045-2322},
support = {CNS2022-135327//Ministerio de Ciencia e Innovación/ ; FORT23/00021//Instituto de Salud Carlos III/ ; },
abstract = {Nowadays, there is an unmet need for reliable and minimally-invasive diagnosis tools capable of detecting Alzheimer's disease at early stages. Such tools could significantly reduce the reliance on confirmatory tests that are invasive and costly, such as cerebrospinal fluid (CSF) biomarkers and neuroimaging. The aim of this study is to validate previously developed diagnosis tools (multivariate models and plasma p-Tau217 levels) in three independents cohorts. For this, a cohort was obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) including some variables (age, Apolipoprotein E (ApoE) genotype, plasma p-Tau217, CSF biomarkers) (n = 113); and two cohorts from cognitive disorders units (Hospital Universitari i Politècnic La Fe (HUiPLaFe, n = 163), Hospital Doctor Peset (n = 31)), whose plasma samples were analysed to determine plasma p-Tau217, and to evaluate the previous diagnosis tools performance. For the cohort from HUiPLaFe, the multivariate model (plasma p-Tau217, age, ApoE genotype) showed a sensitivity of 94.9% and a specificity of 88.2%; for the cohort from Hospital Doctor Peset, the sensitivity was 100% and specificity 80%; for the ADNI cohort, sensitivity was 89.5% and specificity 39.5%. Regarding the plasma p-Tau217 levels, the results were satisfactory for the cognitive disorders units; while ADNI cohort showed very low specificity. In conclusion, the multivariate model was clinically validated in independent cohorts from clinical units, representing its first step for implementation.},
}

@article {pmid41354704,
year = {2025},
author = {Zhou, J and Wan, J and Chen, X and Li, X and Wu, Z and Zhang, Z and Zhang, C},
title = {ViViMZheimer a slice based end to end model for Alzheimer's disease diagnosis from 3D MRI.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-025-29119-7},
pmid = {41354704},
issn = {2045-2322},
support = {No. 20232BAB202022//Jiangxi Provincial natural science fund/ ; No. 2024JJ8004//National Nature Science Foundation of Hunan Province/ ; },
abstract = {Slice-based models have been widely applied in Alzheimer's disease (AD) identification tasks due to their reduced parameter count and fast inference speed. However, existing slice-based models require additional slice extraction steps and cannot achieve an end-to-end process from MRI to diagnostic results. Moreover, they often rely on Transformer architectures to model inter-slice dependencies, which suffer from quadratic computational complexity. To address these limitations, we propose ViViMZheimer, a slice-based end-to-end model that directly processes 3D MRI data and generates diagnostic predictions. ViViMZheimer integrates a ViViT-inspired spatial encoder with a Mamba-based temporal modeling mechanism, maintaining linear computational complexity while effectively capturing inter-slice dependencies along three spatial orientations. Additionally, a lightweight spatial attention module emphasizes lesion-relevant brain regions, and a gated bottleneck convolution refines key features in later stages of the model. We evaluated ViViMZheimer on the ADNI dataset, where it achieved accuracies of 98.17%, 82.21%, and 83.15% in distinguishing AD vs. cognitively normal (CN), AD vs. mild cognitive impairment (MCI), and CN vs. MCI, respectively. These results demonstrate that ViViMZheimer provides an effective and computationally efficient solution for automated Alzheimer's disease diagnosis from 3D MRI scans.},
}

@article {pmid41354678,
year = {2025},
author = {Kumar, BS and Dinesh, BGH and Ganjipete, S and Ramar, M and Ammunje, DN and Kunjiappan, S and Chidambaram, K and Pavadai, P},
title = {Machine learning guided virtual screening of FDA approved drugs targeting GSK-3β in Alzheimer's disease.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-025-28605-2},
pmid = {41354678},
issn = {2045-2322},
abstract = {Alzheimer's disease (AD) remains one of the most challenging neurodegenerative disorders, with limited therapeutic options and high failure rates in clinical trials. This work developed a drug repurposing pipeline powered by a machine learning (ML) model to find possible glycogen synthase kinase-3 beta (GSK-3β) inhibitors, a crucial target in AD pathogenesis. We selected, pre-processed, and optimized a dataset of 4,087 experimentally verified GSK-3β inhibitors using dimensionality reduction and descriptor creation. The most excellent prediction performance was obtained by Random Forest (100 descriptors) out of six supervised ML algorithms that were studied (R[2] = 0.8178, RMSE = 0.8118, MAE = 0.6084). Following the virtual screening of 1,616 Food and Drug Administration (FDA)-approved drugs using this refined model, many compounds with projected IC50 < 500 nM were found. Docking experiments showed insightful interactions and high binding affinities with the active-site residues of GSK-3β. With the best docking score (-9.3 kcal/mol), stable molecular dynamics (Average RMSD values (1000 ns): protein, 2.23 ± 0.93 Å; protein-ligand complex, 1.40 ± 0.43 Å) and long-lasting contacts with crucial residues, dolutegravir stood out among the top choices. ADMET profiling validated good pharmacokinetics and safety characteristics; however, possible hepatotoxicity needs more research. A HOMO-LUMO gap of 3.07 eV was found by density functional theory (DFT) analysis, indicating robust electron transport characteristics and balanced reactivity that are favorable for protein-ligand interaction. Together, these findings show that dolutegravir is a potential repurposable option against AD and how integrative ML, docking, MD, ADMET, and quantum chemistry techniques may speed up the identification of new drugs.},
}

@article {pmid41354641,
year = {2025},
author = {Feyzbakhsh, H},
title = {Nanoparticle-based strategies for overcoming the blood-brain barrier in CNS disorders and brain cancer: precision diagnostics and therapeutics for Alzheimer's, Parkinson's, multiple sclerosis, and glioblastoma.},
journal = {Tissue barriers},
volume = {},
number = {},
pages = {2599564},
doi = {10.1080/21688370.2025.2599564},
pmid = {41354641},
issn = {2168-8370},
abstract = {Nanoparticle (NP)-based technologies are transforming the management of central nervous system (CNS) disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), and brain cancer (BC), glioblastoma, by surpassing the blood-brain barrier (BBB) and blood-brain tumor barrier (BBTB). This review integrates NP approaches, comprising organic (e.g. liposomes, polymeric NPs), inorganic (e.g. gold, iron oxide), carbon-based, and hybrid systems, to overcome disease-specific barriers. In AD, superparamagnetic iron oxide NPs (SPIONs) and gold NPs (AuNPs) improve amyloid-beta plaque and tau protein detection, while liposomes precisely deliver anti-amyloid drugs. For PD, dopamine-loaded liposomes and cerium oxide NPs reinstate dopaminergic function and decrease oxidative stress, with improved motor outcomes. In MS, PEGylated liposomes and PLGA NPs regulate autoimmune responses, inducing remyelination and attenuating neuroinflammation. For BC, dendrimers and magnetic NPs facilitate targeted chemotherapy delivery across the BBB/BBTB, improving glioblastoma treatment outcomes. We compare NP types critically based on physicochemical characteristics, efficacy, toxicity, and clinical translation potential, highlighting gaps in long-term safety and scalability. Challenges like NP toxicity and regulatory complexities are discussed, suggesting biocompatible designs and standardized FDA/EMA pathways. By consolidating diagnostic and therapeutic innovations, this review outlines a roadmap for NP-based precision medicine, paving the way for clinical translation and better patient outcomes in CNS disorders and brain cancer.},
}

@article {pmid41354616,
year = {2025},
author = {Fenelon, A and Chen, J},
title = {Housing Assistance and Health Care Access Among Older Adults with Alzheimer's Disease and Related Dementias: Evidence from Multisource Linked Survey-Administrative Data.},
journal = {The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jagp.2025.11.007},
pmid = {41354616},
issn = {1545-7214},
abstract = {OBJECTIVES: To examine health care access among older adults, with specific attention to the importance of the US Department of Housing and Urban Development (HUD) housing assistance participation and Alzheimer's disease and related dementias (ADRD) diagnosis.

We used a multisource survey-administrative data linkage, combining the 1999-2016 National Health Interview Survey (NHIS), 1999-2018 HUD administrative housing records, and 1999-2018 Medicare enrollment and claims records. The sample included 46,269 NHIS participants aged 65 and above who were linked to the Medicare enrollment and claims file and who were eligible for linkage to the HUD administrative record, regardless of participation in HUD programs.

MEASURES: ADRD status was determined based on a documented diagnosis in Medicare claims. Participation in HUD housing assistance was determined through HUD records. Health care access measures were having no usual source of care, delayed/forgone needed care due to cost, and forgone needed medications due to cost.

RESULTS: Among adults with ADRD, 10% received HUD housing assistance, compared to 5% in the overall sample. Adults with ADRD receiving housing assistance were 2.3 percentage points less likely (95% CI: 1.1-3.7) to report no usual source of care but were more likely to report delayed/forgone care (5.9 percentage points) and forgone medications (4.2 percentage points) compared to those with ADRD but not receiving housing assistance.

CONCLUSIONS: In this nationally representative study of the older adults with ADRD, those receiving housing assistance tended to maintain a usual source of care, but experience cost-related barriers to necessary care.},
}

@article {pmid41354574,
year = {2025},
author = {Flury, A and St-Pierre, MK and Ayata, P and Tremblay, MÈ},
title = {Evolving insights into the identity and function of dark microglia.},
journal = {Trends in neurosciences},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.tins.2025.11.002},
pmid = {41354574},
issn = {1878-108X},
abstract = {Microglia are the brain's primary innate immune cells, which maintain neural homeostasis through surveillance, debris clearance, and synaptic remodeling. Dark microglia represent a distinct state of microglia that came into recent focus due to their excessive physical contact with synapses in contexts of pathological synapse loss, predominantly in neurodegenerative conditions, such as Alzheimer's disease. Dark microglia are identified by their unique ultrastructural features, exhibiting a dark, condensed appearance under electron microscopy. They display signs of cellular stress and appear to be engaged in synaptic pruning. Here, we review recent advances in understanding these intriguing cells in the mammalian brain, from new molecular insights into their origin to their emerging functional roles across the lifespan, in both health and disease.},
}

@article {pmid41354561,
year = {2025},
author = {Lan, S and Gao, F and Ji, R and Wang, Z and Zang, Z and Wei, Y and Kuang, H and Wang, Z},
title = {Corrigendum to "Bushen Yinao pill improves cognitive function in Alzheimer's disease rats by regulating PI3K/Akt pathway and intestinal microbiota" [Fitoterapia 188 (2026) 106999].},
journal = {Fitoterapia},
volume = {},
number = {},
pages = {107019},
doi = {10.1016/j.fitote.2025.107019},
pmid = {41354561},
issn = {1873-6971},
}

@article {pmid41354326,
year = {2025},
author = {Wiredu, K and Gowda, P and Rhee, J and Mueller, A and Simon, C and Graves, OK and Qu, JZ and Spite, M and McKay, TB and Akeju, O},
title = {Long-chain polyunsaturated fatty acid lipid and oxylipin alterations in postoperative delirium after cardiac surgery.},
journal = {Journal of lipid research},
volume = {},
number = {},
pages = {100959},
doi = {10.1016/j.jlr.2025.100959},
pmid = {41354326},
issn = {1539-7262},
abstract = {Lipids play a crucial role in signaling, membrane dynamics, and inflammatory regulation, yet their involvement in postoperative delirium pathogenesis remains unclear. This study examined serum lipidomic alterations in postoperative delirium and assessed the effects of dexmedetomidine treatment on these changes. Lipidomic profiling was conducted at baseline and postoperative day one in two independent cohorts of cardiac surgery patients. Mass spectrometry-based shotgun lipidomics and targeted lipid analyses were used to assess lipidomes and oxylipins, respectively. Cardiac surgery was associated with decreased serum lysophospholipids. Postoperative delirium was associated with increased long-chain polyunsaturated fatty acid phospholipids (LCPUFA-PLs), particularly phosphatidylethanolamines (PEs), and elevated oxylipins. Dexmedetomidine, a potential delirium-mitigating medication, reduced LCPUFA-PLs. These findings highlight lipid modulation as a potential target for postoperative delirium prevention.},
}

@article {pmid41354147,
year = {2025},
author = {Singh, A and Pettini, F and Gianibbi, B and Das, S and Barisani, D and Purslow, JA and Furini, S and Spiga, O and Venditti, V},
title = {Structure-based discovery of a non-competitive FTO inhibitor bound to a cryptic site at the domain interface.},
journal = {Journal of molecular biology},
volume = {},
number = {},
pages = {169575},
doi = {10.1016/j.jmb.2025.169575},
pmid = {41354147},
issn = {1089-8638},
abstract = {The fat mass and obesity-associated fatso (FTO) protein is a member of the AlkB family of dioxygenases whose overexpression links to several metabolic diseases, including obesity, type 2 diabetes, Alzheimer's, and various types of cancer. FTO is an important target for pharmaceutical research, and several selective and non-selective competitive inhibitors have been developed against the enzyme. However, given the competitive nature of the available inhibitors, obtaining complete subfamily selectivity still presents an unresolved challenge. Here, we describe the discovery of a molecular scaffold for selective inhibition of FTO, which resulted from high throughput virtual screening targeted at FTO cryptic pockets. Analysis of the FTO-inhibitor interaction by solution NMR, molecular dynamics simulations, and enzyme kinetic assays shows that, differently from the FTO inhibitors developed so far, our molecule binds to a cryptic site between the FTO structural domains, and modulates the enzyme function non-competitively by perturbing the binding pose of the α-ketoglutarate and nucleic acid substrates. Since FTO is the only member of the AlkB family that presents multiple structural domains, we expect further development of this allosteric molecule to result in a new family of highly selective FTO inhibitors that can be used alone or in combination with pre-existing compounds to improve their potency and selectivity.},
}

@article {pmid41354142,
year = {2025},
author = {Elkana, O and Segal, O and Beheshti, I and , },
title = {Beyond brain scans: verbal memory testing as an efficient cognitive biomarker for preclinical Alzheimer's disease.},
journal = {Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuroscience.2025.12.008},
pmid = {41354142},
issn = {1873-7544},
abstract = {Timely and accessible tools for detecting preclinical Alzheimer's disease (AD) are essential for early intervention, yet reliance on MRI biomarkers limits scalability. Using longitudinal data from 210 cognitively normal older adults in ADNI, we compared the predictive value of verbal episodic memory, hippocampal volume, and a visuospatial composite. Over a 7-year window, 106 participants progressed to mild cognitive impairment (MCI), while 104 remained stable. At baseline, Immediate Recall on the Rey Auditory Verbal Learning Test was the strongest predictor of progression (AUC = 0.71), outperforming hippocampal volume (AUC = 0.66) and visuospatial scores (AUC = 0.57). Longitudinal models confirmed a steeper decline in converters (p < 0.001), underscoring its sensitivity to preclinical disease dynamics. Immediate recall accurately detected subtle functional changes, achieving predictive performance highly comparable to MRI-based hippocampal measurements. Immediate Recall is brief, low-cost, and has the potential for digital adaptation, making it a scalable tool for early detection and monitoring of cognitive changes. It could be deployed online or in community-based care where advanced diagnostics are limited. ONE SENTENCE SUMMARY: Immediate verbal recall outperforms hippocampal volume and visuospatial measures in predicting conversion to mild cognitive impairment, offering a scalable, low-cost tool for early detection in aging populations.},
}

@article {pmid41354093,
year = {2025},
author = {Alpert, JM and Kovach, JD and Casacchia, NJ and Harris, D and Hashmi, A and Kim, LD and Perez-Protto, S and Pappas, MA and Rothberg, MB},
title = {Hospitalization Experiences Among Nursing Home Residents With Dementia.},
journal = {Journal of the American Medical Directors Association},
volume = {},
number = {},
pages = {106022},
doi = {10.1016/j.jamda.2025.106022},
pmid = {41354093},
issn = {1538-9375},
abstract = {OBJECTIVES: Hospital admissions among nursing home residents with Alzheimer's disease and related dementias (ADRD) are burdensome, expensive, and provide limited clinical benefit. Compared with other patients, those with ADRD are more likely to experience adverse events when hospitalized. Our objective was to comprehensively describe the in-hospital experience of nursing home patients with ADRD.

DESIGN: We analyzed 1 randomly selected hospitalization per patient from the electronic health record.

SETTING AND PARTICIPANTS: Adult patients with an ADRD diagnosis from a single health system in Ohio and Florida who resided in a nursing home and were transferred to a hospital from January 2013 to July 2023.

METHODS: Descriptive statistics for each variable.

RESULTS: Of 10,195 patients, median age was 84 years, 71% were White, 61% were female, and median length of stay was 5 days. During the hospitalization, 69% required a sitter, 34% a Foley catheter, 21% were diagnosed with delirium, and 4% died. Six percent were put in restraints, 4% experienced a fall, and 51% were administered at least 1 neuropsychiatric medication. Fewer than half of all patients (45%) had a do-not-resuscitate order, 5% had a consultation with palliative care, 2.4% with geriatrics, and 1.1% with hospice. Nearly 20% of all patients were admitted to the intensive care unit (ICU). Of these, 58% had do-not-resuscitate orders, 78% required a sitter, 53% had delirium, 17% had an order for restraints, 62% had a Foley catheter, and 10% had a long-term feeding tube inserted. Ten percent of ICU patients had a consultation with palliative care, 3.4% with geriatrics, and 2.2% with hospice.

CONCLUSIONS AND IMPLICATIONS: Patients undergoing hospital admission suffered distressing experiences, but most patients did not have do-not-resuscitate orders, and referrals to hospice and palliative care were rare. Patients and their family members should be informed about the hospital experience before admission and offered appropriate care services.},
}

@article {pmid41353938,
year = {2025},
author = {Palma, A and Di Natale, C and Tammaro, D and Lagreca, E and Giordano, G and Russo, S and Vitiello, G and Ferraro, V and Vespini, V and Grilli, S and Maffettone, PL and Coppola, S},
title = {Colorimetric sensing for transdermal phospho-Tau 181 detection mediated by wearable microneedle functionalized with gold nanoparticle (MN-AuNP).},
journal = {Talanta},
volume = {300},
number = {},
pages = {129198},
doi = {10.1016/j.talanta.2025.129198},
pmid = {41353938},
issn = {1873-3573},
abstract = {Microneedles (MNs) have rapidly emerged as powerful tools in wearable biosensing, providing minimally invasive access to interstitial fluid (ISF). Among the neurodegenerative based biomarkers detectable in ISF, phosphorylated Tau at threonine 181 (p-Tau181) is reaching a clinically evaluable significance for Alzheimer's disease (AD) and other tauopathies. Elevated p-Tau181 levels are strongly correlated with abnormal Tau aggregation in the brain and with cognitive decline. Current diagnostic methods rely on invasive cerebrospinal fluid (CSF) sampling or costly laboratory immunoassays and radio-imaging which are unsuitable for routine or point-of-care screening. Here, we present a highly sensitive colorimetric microneedle-based immunosensor designed for non-invasive, transdermal detection of p-Tau181. For the first time, gold nanoparticles (AuNPs) are integrated into a three-dimensional (3D) microneedle geometry, where antibody antigen recognition occurs directly on MN in contact with ISF. The aggregation-induced optical shifts of AuNPs provide an immediate and instrument-free colorimetric signal, while two optimized coating techniques enable uniform immobilization and reproducible performance. The MN-AuNP platform achieves a limit of detection (LoD) of 16 pg/mL, a nearly 30-fold improvement compared to the reported 2D surface (460 pg/mL). This enhancement shoots from the 3D architecture, which offers greater surface area, enhanced probe loading, and improved analyte diffusion. Compared with existing diagnostic approaches, the proposed system offers multiple advantages: non-invasive operation, real-time readout without complex instrumentation, low fabrication cost, and potential integration into wearable or point-of-care formats. Collectively, these results lay the groundwork for advanced MN-based colorimetric biosensors for early Alzheimer's disease detection through accessible and patient-friendly neurodiagnostic technologies.},
}

@article {pmid41353931,
year = {2025},
author = {Song, ZL and Osama, A and Ji, M and He, Q and Zhang, B and Zhao, H and Hu, Y and Cai, W and Fang, J},
title = {Emerging of a new neuroprotective isoflavonoid with potent Keap1/Nrf2/ARE pathway activation and AChE inhibition.},
journal = {Bioorganic chemistry},
volume = {168},
number = {},
pages = {109336},
doi = {10.1016/j.bioorg.2025.109336},
pmid = {41353931},
issn = {1090-2120},
abstract = {Several neurodegenerative disorders (NDDs), including Alzheimer's disease (AD), are characterized by disrupted redox balance and impaired cholinergic signaling. Activation of nuclear factor erythroid 2-related factor 2 (Nrf2) pathway to restore redox equilibrium has been recognized as a potential strategy to counteract progressive neuronal degeneration; also, preserving the available levels of acetylcholine through acetylcholinesterase (AChE) inhibition, may largely alleviate cognitive malfunction in patients. In our continued efforts to discover effective neuroprotective drug leads, a library of 23 isoflavonoid derivatives and 10 deoxybenzoin intermediates was currently prepared and comprehensively evaluated for antioxidant capacity and potential neuroprotection. Among these compounds, compound 32 demonstrated the strongest activity, exhibiting robust neuroprotection against both H2O2- and scopolamine-induced injury in PC12 cells. Notably, it markedly upregulated vital antioxidant defense systems and efficiently inhibited the AChE (IC50 = 14.79 μM), surpassing the efficacy of the reference drug rivastigmine (IC50 = 24.5 μM). The mechanism studies showed its neuroprotection mainly relies on Nrf2 activation. Furthermore, compound 32 significantly ameliorated memory impairment and the neuroinflammation associated with scopolamine-initiated cognitive dysfunction in a zebrafish model. Collectively, this study identifies compound 32 as a promising dual-acting neuroprotective lead, offering potential value for advancing therapeutic strategies in AD drug development.},
}

@article {pmid41353886,
year = {2025},
author = {Bukreeva, I and Junemann, O and Palermo, F and Fratini, M and Gigli, G and Karpov, D and Saveliev, SV and Cedola, A},
title = {Machine learning approaches to reveal pinealocyte changes in ageing and Alzheimer's disease.},
journal = {Computers in biology and medicine},
volume = {200},
number = {},
pages = {111362},
doi = {10.1016/j.compbiomed.2025.111362},
pmid = {41353886},
issn = {1879-0534},
abstract = {This study investigates age-related changes in human pinealocytes and their association with Alzheimer's disease (AD). We analyzed calcified deposits in the pineal gland (PG) using a novel approach combining X-ray nano-holotomography and convolutional neural network-based image processing. Our approach used a U-net architecture for PG morphological feature segmentation, with particular emphasis on micro-calcifications in the pinealocyte cytoplasm, identified as primary calcification sites. The ratio of cytoplasmic deposits to number of pinealocytes in tissue volume showed a weak negative age-related tendency, but was not associated with AD. Our results show that pineal calcification may serve as a biomarker for synthetic activity, which declines with age. In addition, pathology-specific factors associated with AD may modulate pineal calcification patterns, potentially confounding age-related trends. Our findings contribute to a broader understanding of age-related neuropathology by providing insight into pineal alterations at the cellular level.},
}

@article {pmid41353868,
year = {2025},
author = {Duarte, TA and Ng, CP and Salvador, JAR and Pipito, L and Greaves, J and Moreira, VM},
title = {S-acylation and neuroinflammation: the therapeutic potential of zDHHC and deacylase modulation.},
journal = {European journal of medicinal chemistry},
volume = {303},
number = {},
pages = {118429},
doi = {10.1016/j.ejmech.2025.118429},
pmid = {41353868},
issn = {1768-3254},
abstract = {Neuroinflammation is a hallmark of many neurodegenerative diseases, including Alzheimer's, Parkinson's and Huntington's disease, multiple sclerosis, and infantile neuronal ceroid lipofuscinosis. Dynamic protein S-acylation, a reversible lipid post-translational modification, is an important regulator in these processes. S-acylation is catalysed by the zDHHC palmitoyl acyltransferases, and removal of the acyl groups is mediated by acyl-protein thioesterases. S-acylation controls the localisation, stability, and function of around 48 % of all proteins in the nervous system, including synaptic scaffolds, ion channels, immune receptors, and trafficking proteins. Moreover, dysregulated S-acylation contributes to synaptic loss, aberrant immune signalling, and neurodegeneration. This review examines proteins implicated in neuroinflammation with reported S-acylase or deacylase activity, outlines current knowledge on disease-related alterations in S-acylation, and assesses the therapeutic promise of available small-molecule modulators. Linking the activity of these enzymes with human disease highlights the potential of reversible S-acylation as a source of innovative targets for drug discovery in neuroinflammation.},
}

@article {pmid41353845,
year = {2025},
author = {Azadmaleki, H and Zolnour, A and Rashidi, S and Noble, JM and Hirschberg, J and Esmaeili, E and Morovati, T and Zolnoori, M},
title = {TransformerCARE: A novel speech analysis pipeline using transformer-based models and audio augmentation techniques for cognitive impairment detection.},
journal = {International journal of medical informatics},
volume = {207},
number = {},
pages = {106208},
doi = {10.1016/j.ijmedinf.2025.106208},
pmid = {41353845},
issn = {1872-8243},
abstract = {OBJECTIVE: Early diagnosis of cognitive impairment, including Alzheimer's and other dementias, is critical for effective treatment and slowing disease progression. However, over 50% of cases remain undiagnosed until advanced stages due to limitations in current methods. Recognizing speech impairments as early markers of cognitive decline, this study evaluated the utility of speech analysis as a technique for early detection. We introduce TransformerCARE, a speech processing pipeline utilizing advanced speech transformer models.

METHODS: TransformerCARE incorporated a series of key steps, including preprocessing, speech segmentation, transformer fine-tuning, segment aggregation, performance evaluation, and data augmentation. In the fine-tuning step, we evaluated the performance of four state-of-the-art speech transformer models: Wav2vec 2.0, HuBERT, WavLM, and DistilHuBERT. For data augmentation, we adopted multiple techniques, with particular emphasis on frequency masking due to its ability to preserve subtle acoustic cues associated with cognitive impairment. We measured the performance of TransformerCARE on the ADReSSo Challenge dataset from DementiaBank, comprising 237 subjects (122 cognitively impaired and 115 cognitively normal).

RESULTS: TransformerCARE demonstrated its highest performance with HuBERT, achieving an AUC of 81.80 (F1-score = 79.31) using an aggregation technique that averaged embeddings of 14-second speech segments. Augmenting the training data with frequency masking improved performance by 5 %, resulting in an AUC of 86.11 (F1-score = 84.63). We also demonstrated that incorporating clinicians' speech during patient interactions can improve the performance of the pipeline. Our error analysis revealed significant differences between the acoustic patterns of correctly identified negative cases (true negatives) and those incorrectly identified as positive (false positives), as well as between correctly identified positive cases (true positives) and those incorrectly identified as negative (false negatives). This indicates specific deviations in speech characteristics among inaccurately diagnosed subjects.

CONCLUSION: In summary, TransformerCARE demonstrates strong potential for integration into clinical workflows as a screening tool for cognitive impairment, aiding in the timely and appropriate care of affected patients.},
}

@article {pmid41353692,
year = {2025},
author = {Bhunia, PK and Kasturi, P},
title = {Meta-analysis of extracellular vesicles-associated protein abundance and aggregation during aging and disease in C. elegans.},
journal = {Biogerontology},
volume = {27},
number = {1},
pages = {13},
pmid = {41353692},
issn = {1573-6768},
support = {BT/RLF/Re-entry/31/2018//Department of Biotechnology, Ministry of Science and Technology, India/ ; },
mesh = {*Extracellular Vesicles/metabolism ; *Caenorhabditis elegans/metabolism ; Animals ; *Aging/metabolism ; *Caenorhabditis elegans Proteins/metabolism ; Protein Aggregates ; Humans ; Proteome/metabolism ; Proteostasis ; },
abstract = {Extracellular vesicles (EVs) contribute to the maintenance of organism-wide proteostasis by mediating intercellular communication. Loss of proteostasis and altered intercellular communication are associated with aging and age-related diseases, suggesting key roles for EVs. However, it is unclear how the proteome of the EVs changes with age. To identify EV-associated proteins (EVAPs) and their fate with age, we curated publicly available EV proteome data from C. elegans model organism and human. Our analysis reveals that EVs carry proteins with diverse functions, including those involved in protein quality control. We found that abundance of the EVAPs changes significantly with age, heat stress, pathogen infections and diseases. Many of these EVAPs also aggregate with age and overlap with Aβ-driven protein aggregates. Further, we identified human orthologs of C. elegans EVAPs from human brain tissues affected with Alzheimer's disease and breast cancer. This meta-analysis highlights EVs proteome composition, their abundance changes, and aggregation during aging, stress, infection and disease conditions. Overall, this study provides new insights into the dynamics of EV proteins during aging and may possibly help in identifying potential biomarkers for age-related diseases.},
}

*Extracellular Vesicles/metabolism
*Caenorhabditis elegans/metabolism
Animals
*Aging/metabolism
*Caenorhabditis elegans Proteins/metabolism
Protein Aggregates
Humans
Proteome/metabolism
Proteostasis

@article {pmid41353558,
year = {2025},
author = {Dadras, S and Bhaskar, K},
title = {Global Deficiency of Alzheimer's Disease Risk Gene Il1rap Reduces Pathological Tau in a Mouse Model of Systemic Inflammation.},
journal = {ASN neuro},
volume = {17},
number = {1},
pages = {2598310},
doi = {10.1080/17590914.2025.2598310},
pmid = {41353558},
issn = {1759-0914},
mesh = {Animals ; *tau Proteins/metabolism/genetics ; Mice ; *Alzheimer Disease/genetics/metabolism/pathology ; Disease Models, Animal ; *Interleukin-1 Receptor Accessory Protein/genetics/deficiency ; *Inflammation/metabolism/genetics/pathology/chemically induced ; Mice, Knockout ; Mice, Inbred C57BL ; Lipopolysaccharides/toxicity ; Neurons/metabolism ; Male ; },
abstract = {Brain inflammation is strongly associated with neurodegeneration in Alzheimer's disease (AD) and related tauopathies. We have previously demonstrated that microglia-derived interleukin-1β (IL-1β) induces tau hyperphosphorylation in a cell-autonomous manner and depends on activating the IL-1 receptor (IL-1R1) signaling pathway. IL-1 receptor accessory protein (IL-1RAcP) is a co-receptor for IL-1R1 and is essential for the IL-1R1 receptor function and downstream signaling. Genome-wide association studies have identified several single-nucleotide polymorphisms (SNPs) in the IL1RAP gene that have been shown to increase AD risk. Here, we demonstrate that global and neuron-specific isoform deficiency of IL-1RAcP regulates hyperphosphorylated tau levels in a lipopolysaccharide (LPS)-induced mouse model of systemic inflammation. Notably, while global Il1rap[-/-] reduced pS202(AT8) and pT231 (AT180) tau levels, neuron-specific IL-1RAcP (IL-1RAcPb) deficiency specifically increased total tau levels. Together, these results suggest that IL-1RAcP is an important regulator of tau hyperphosphorylation relevant to AD and related tauopathies.},
}

Animals
*tau Proteins/metabolism/genetics
Mice
*Alzheimer Disease/genetics/metabolism/pathology
Disease Models, Animal
*Interleukin-1 Receptor Accessory Protein/genetics/deficiency
*Inflammation/metabolism/genetics/pathology/chemically induced
Mice, Knockout
Mice, Inbred C57BL
Lipopolysaccharides/toxicity
Neurons/metabolism
Male

@article {pmid41353509,
year = {2025},
author = {Kolouei, A and Barati, M and Abbas-Mohammadi, M},
title = {Investigating the binding potential of the Melissa officinalis oil against Alzheimer's targets by molecular docking and in vitro evaluations.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-025-30232-w},
pmid = {41353509},
issn = {2045-2322},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder with limited treatment options. Melissa officinalis (M. officinalis), traditionally used for its medicinal properties, contains compounds that may offer therapeutic benefits for AD. We extracted essential oils from M. officinalis using supercritical CO2 and identified 31 compounds via GC-MS, supplemented by 20 non-volatile compounds from the Dictionary of Natural Products. Molecular docking was performed against five AD-related targets: β-Secretase, γ-Secretase, amyloid-β) A(, neprilysin, and acetylcholinesterase. The oil's antioxidant capacity and cytotoxicity on PC12 cells were evaluated using DPPH and MTT assays, respectively. Docking analysis revealed that sajerinic acid had the highest affinity for acetylcholinesterase, neprilysin, and γ-Secretase. Aβ and β-Secretase were most affected by 3',4',5,7-tetrahydroxyflavone, 3'-O-β-D-glucuronopyranoside, γ-O-β-D-glucopyranoside and 2,3,19,23-tetrahydroxy-12-ursen-28-oic acid-23-sulfate, 28-O-β-D-glucopyranosyl ester, respectively. Among oil compounds, triethyl citrate showed the highest affinity for β-Secretase, neprilysin, and γ-Secretase, while 2,2-dimethoxybutane exhibited the highest potential for interaction with Aβ and acetylcholinesterase. The oil reduced PC12 cell survival in a dose-dependent manner. The extract also displayed significant antioxidant activity, suggesting a potential to reduce oxidative stress. These findings suggest that M. officinalis contains compounds with potential anti-Alzheimer's properties, warranting further investigation. The identified compounds could serve as leads for developing novel therapeutics, and the antioxidant activity of the extract supports its traditional use in managing neurodegenerative conditions. Further studies are needed to validate these findings in vivo and explore the therapeutic potential of M. officinalis in AD.},
}

@article {pmid41353403,
year = {2025},
author = {Bhargavan, B and Annadurai, N and Kanmogne, GD},
title = {Glycogen synthase kinase-3 activation and dysregulation of amyloid transport receptors expression and shedding in HIV-induced Alzheimer's disease-like pathology: modulatory effects of CCR5 antagonists.},
journal = {Acta neuropathologica communications},
volume = {},
number = {},
pages = {},
doi = {10.1186/s40478-025-02197-4},
pmid = {41353403},
issn = {2051-5960},
support = {1R21 MH123303 and 1R01 MH132517/MH/NIMH NIH HHS/United States ; },
}

@article {pmid41353310,
year = {2025},
author = {Potvin-Jutras, Z and Tremblay, PL and Mohammadi, H and Villeneuve, S and Spreng, RN and Gauthier, CJ and , },
title = {Longitudinal effects of cerebrovascular reactivity and cerebral pulsatility in cognitively intact older adults with APOE4: links with cognition.},
journal = {GeroScience},
volume = {},
number = {},
pages = {},
pmid = {41353310},
issn = {2509-2723},
support = {RGPIN-2024-06455//Natural Sciences and Engineering Research Council of Canada/ ; 468740/CAPMC/CIHR/Canada ; AARG- 22-927100/ALZ/Alzheimer's Association/United States ; NIA R01 AG068563/NH/NIH HHS/United States ; },
abstract = {The apolipoprotein E4 (APOE4) allele is the strongest genetic risk factor for Alzheimer's disease (AD) and is linked to poorer cerebrovascular health. Cerebrovascular reactivity (CVR), an indicator of vascular reserve, and cerebral pulsatility (CP), a marker of vascular stiffness, are sensitive biomarkers of early vascular dysfunction associated with aging and AD. However, the relationship between APOE4 status and these cerebrovascular metrics remains unclear. This study investigated whether the APOE genotype influences longitudinal changes in CVR and CP, and their association with cognitive performance in cognitively unimpaired individuals. We utilized the PREVENT-AD cohort, including 101 APOE4 carriers (30 males and 71 females) and 152 non-APOE4 carriers (48 males and 104 females) aged 55 and older. Relative CVR and CP were derived from resting state functional magnetic resonance imaging data, with regional values extracted from cerebral arterial territories. Results indicated significant interactions between APOE4 status and relative CVR in the left middle cerebral artery and left posterior cerebral artery (PCA) territories. APOE4 status disaggregated analyses revealed that APOE4 carriers uniquely presented a significant decline in relative CVR within the left PCA. Furthermore, sex-specific effects were identified, with female APOE4 carriers having lower relative CVR in the right anterior cerebral artery territory compared to female non-carriers. Importantly, higher relative CVR was positively associated with better cognitive performance in APOE4 carriers. No significant effects of APOE4 status on CP were found. Together, these findings suggest that relative CVR may be an important early measure of cerebrovascular health and cognition in cognitively intact APOE4 carriers.},
}

@article {pmid41352683,
year = {2025},
author = {Shim, GH and Lau, ECY and Huynh, ALH and Lu, CY and Tan, ECK},
title = {Influence of patient characteristics on efficacy and safety of anti-amyloid monoclonal antibodies in Alzheimer's disease: A systematic review and meta-analysis.},
journal = {Ageing research reviews},
volume = {114},
number = {},
pages = {102981},
doi = {10.1016/j.arr.2025.102981},
pmid = {41352683},
issn = {1872-9649},
abstract = {BACKGROUND: Lecanemab and donanemab are the first anti-amyloid monoclonal antibodies (mAbs) clinically available as disease-modifying therapies for Alzheimer's disease (AD). However, it remains unclear whether their treatment effects differ across demographic, clinical, or genetic subgroups.

OBJECTIVE: This systematic review aimed to explore how patient characteristics modify the efficacy, safety and humanistic outcomes of anti-amyloid mAbs lecanemab and donanemab in patients with early AD.

METHODS: A systematic search of MEDLINE, Embase, Scopus, Web of Science, and Cochrane Library was conducted from database inception to July 30th, 2025, using a combination of keywords and Medical Subject Heading terms relating to lecanemab and donanemab. Meta-analyses were conducted for safety outcomes where sufficient data was available.

RESULTS: Sixteen studies representing six randomised clinical trials (total N = 5633) were included. Both lecanemab and donanemab showed the greatest slowing of cognitive decline in White/Caucasian patients and apolipoprotein E4 (ApoE4) non-carriers. Amyloid-related imaging abnormalities with edema/effusion (ARIA-E) and microhemorrhages (ARIA-H) were more prevalent in ApoE4 carriers. The risk of ARIA-E was 2.19 times higher (95 %CI:1.91-2.50) and ARIA-H was 3.45 times higher (95 %CI:1.35-8.72) in ApoE4 carriers versus non-carriers. Statistically significant improvements in health-related quality of life were observed with lecanemab in ApoE4 heterozygous participants and in those aged 65-74 years.

CONCLUSIONS: The efficacy and safety of anti-amyloid mAbs in AD may differ based on patients' demographic and genetic factors. These findings highlight the potential for personalised treatment strategies and inform national drug policies. Further research is needed to evaluate long-term outcomes and address under-studied patient populations.

SUMMARY: The efficacy and safety of lecanemab and donanemab varied across patient subgroups, including age, sex, race/ethnicity and genetic factors such as ApoE4 genotype status. The risk of ARIA was higher in ApoE4 carriers, particularly the homozygous.},
}

@article {pmid41352634,
year = {2025},
author = {Geleta, LA and Doyle, C and Garton, FC and Fowler, M and Carr, JM and Akkari, PA and McRae, AF and Rogers, ML and Madakkatel, I and Benyamin, B},
title = {The roles of human endogenous retrovirus in neurodegenerative diseases: A systematic review.},
journal = {Brain, behavior, and immunity},
volume = {132},
number = {},
pages = {106201},
doi = {10.1016/j.bbi.2025.106201},
pmid = {41352634},
issn = {1090-2139},
abstract = {BACKGROUND: Human endogenous retroviruses (HERVs) constitute ∼8 % of the human genome, far exceeding the 2 % occupied by protein-coding genes. Although most HERV sequences are inactive, some HERV elements can be reactivated under certain conditions and may contribute to neurodegenerative diseases (NDDs). However, the findings vary across different HERV families, disease models, and detection methods. Here, we systematically review and synthesize the available evidence on the role of HERVs in human NDDs and reconcile inconsistencies in the literature.

METHODS: We systematically searched MEDLINE, EMBASE, Cochrane Library, PsycINFO, Scopus, Web of Science, CINAHL, and Emcare to identify relevant studies. Two independent reviewers screened studies, assessed quality, and extracted data. Qualitative synthesis was conducted for all included NDDs, specifically Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Parkinson's disease (PD), and due to data availability, meta-analysis was used to assess the impact of HERVs antibodies on ALS only.

RESULTS: Twenty-six studies (N ranges: 6-485) met the inclusion criteria, with majority focusing on HERV-K and ALS. Across studies, the association between HERV expression and NDDs was inconsistent, particularly for ALS, PD, and FTD, whereas investigations in AD showed a more consistent upregulation of specific HERVs. Studies relying on polymerase chain reaction (PCR) (typically smaller) showed inconsistent associations (21 studies), while RNA sequencing studies reported consistent associations (9 studies). A preliminary meta-analysis revealed a fivefold increase [OR: 5.83; 95 % CI: 4.14, 8.18] in ALS risk among participants with positive HERV antibodies.

CONCLUSIONS: The inconsistencies in HERV involvement across NDDs highlight the need for further studies employing standardized methodologies. RNAseq findings on the association of HERVs expression and NDDs support the need for large-scale RNA sequencing studies (rather than small, PCR studies) and careful tissue selection to clarify HERVs' role in NDDs. The association of HERV-K antibodies with ALS risk and prognosis suggests a significant role in disease, which could help detect biomarkers and used as a target for treatment.},
}

@article {pmid41352453,
year = {2025},
author = {Chen, X and Gan, L and Huang, Y and Wei, SH and Wang, W and Huang, Y},
title = {Exploring the roles of AKR1C1, AKR1C2, and AKR1C3 in the nervous system: Mechanisms and perspectives.},
journal = {Experimental neurology},
volume = {},
number = {},
pages = {115580},
doi = {10.1016/j.expneurol.2025.115580},
pmid = {41352453},
issn = {1090-2430},
abstract = {Aldo-keto reductase 1C (AKR1C) enzymes, including AKR1C1, AKR1C2, and AKR1C3, play crucial roles in the metabolism of steroid hormones and prostaglandins through their catalytic activities. Although their functions have been extensively studied in endocrine tissues and hormone-dependent malignancies, their significance in the nervous system remains underexplored. Emerging evidence suggests that AKR1C enzymes regulate neurosteroid homeostasis, modulate GABAergic neurotransmission, support synaptic plasticity, and participate in cellular defense against oxidative stress. These multifaceted activities implicate AKR1C1-C3 in diverse neural processes, including neuroprotection, emotional regulation, and neurodevelopment. Furthermore, the potential involvement of AKR1C1, AKR1C2, and AKR1C3 in neurodegenerative diseases such as Alzheimer's, Parkinson's, and Huntington's disease suggests their possible therapeutic relevance. This review consolidates current findings on the molecular characteristics, brain region-specific expression, and neurophysiological functions of AKR1C enzymes, and discusses their emerging roles in central nervous system disorders. By presenting these insights, this review offers a valuable framework for researchers to explore new directions in the development of neuroprotective and neuroregenerative strategies.},
}

@article {pmid41352060,
year = {2025},
author = {Liu, Y and Zhang, C and Wang, X and Shao, Y and Cai, X and Liu, H and Zhu, HL and Liu, X and Qian, Y and Wang, X},
title = {Ultra-large stokes shift probe enables SIM super-resolution tracking of lysosomal acidification impairment in Aβ trafficking dysregulation during Alzheimer's disease.},
journal = {Biosensors & bioelectronics},
volume = {295},
number = {},
pages = {118284},
doi = {10.1016/j.bios.2025.118284},
pmid = {41352060},
issn = {1873-4235},
abstract = {Lysosomal acidification deficits are increasingly recognized as early events in Alzheimer's disease (AD), yet tools for real-time pH monitoring remain limited. Here, we report AHP, a pH-sensitive fluorescent probe with rapid response (ΔpH ≥0.2), high lysosomal specificity, ultra-large Stokes shift (>240 nm), and excellent photostability for long-term imaging. AHP enabled visualization of biphasic Aβ42-induced lysosomal pH dysregulation-initial hyperacidification followed by pathological alkalinization-directly linking acidification failure to impaired Aβ42 clearance. Dual-channel live imaging showed that reduced lysosomal acidity disrupts Aβ42 degradation, leading to cytoplasmic accumulation and increased toxicity.Using AHP-based high-throughput screening, we identified protocatechuic aldehyde as a lysosomal acidification enhancer and validated its efficacy in restoring autophagic flux. As the probe to achieve super-resolution tracking of lysosomal pH in neurodegeneration, AHP connects pH dynamics with AD pathogenesis and offers a powerful tool for mechanistic insight and drug discovery.This work establishes lysosomal pH homeostasis as a critical target in early AD intervention and highlights the broad applicability of AHP in aging-related disorders.},
}

@article {pmid41352005,
year = {2025},
author = {Nguyen, C and Cheung, KCP and Chen, X and Saint-Pol, J and Shimizu, F and Kanda, T and Pot, C and Culot, M and Chan, KWY and Lu, W and Lyu, A and Jia, W and Gosselet, F},
title = {Metabolic profiles of the human blood-brain barrier cells treated by TNF-alpha and oxysterols.},
journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie},
volume = {193},
number = {},
pages = {118853},
doi = {10.1016/j.biopha.2025.118853},
pmid = {41352005},
issn = {1950-6007},
abstract = {The blood-brain barrier (BBB) is essential for central nervous system homeostasis, and its dysfunction is implicated in neuroinflammatory disorders such as Alzheimer's disease and multiple sclerosis. Oxysterols, cholesterol-derived metabolites, modulate lipid metabolism, immune responses, and BBB physiology, but their specific metabolic effects remain poorly defined. Using an in vitro human BBB model, we examined the impact of tumor necrosis factor-α (TNFα) and selected oxysterols (24S-hydroxycholesterol, 25-hydroxycholesterol, 7α,25-dihydroxycholesterol) on metabolomic profiles of brain-like endothelial cells (hBLEC) and pericytes (hBP) via targeted LC-MS/MS analysis of over 300 metabolites. TNFα markedly increased phenylpyruvic acid, indicating dysregulated phenylalanine metabolism. Oxysterols elicited minimal effects in hBLEC, but significantly altered glycolysis and fatty acid metabolism in hBP, notably reducing fructose 6-phosphate, glucose 6-phosphate, and myristoleic acid, while increasing specific fatty acids under inflammatory conditions. These results identify phenylpyruvic acid as a candidate biomarker of BBB inflammation and highlight pericyte metabolic reprogramming as a key mechanism of oxysterol action.},
}

@article {pmid41351905,
year = {2025},
author = {Vandersteen, C and Plonka, A and Derreumaux, A and Ramette, M and Payne, M and Castillo, L and Guevara, N and Robert, P and Manera, V and Gros, A},
title = {Kinematic handwriting impairments in olfactory dysfunction-related post-acute covid syndrome: short and long-term neurophysiological considerations.},
journal = {Brain and cognition},
volume = {193},
number = {},
pages = {106383},
doi = {10.1016/j.bandc.2025.106383},
pmid = {41351905},
issn = {1090-2147},
abstract = {BACKGROUND: Post-Acute COVID-19 Syndrome (PACS) frequently includes persistent olfactory dysfunction (OD) and may share neurocognitive features with Alzheimer's disease (AD). While fine motor impairments in handwriting are established in AD, they have not been systematically investigated in PACS.

METHODS: In this prospective-retrospective study, handwriting kinematics from 30 patients with OD-related PACS were compared with those of 30 healthy participants (HP) matched for age, sex, and education. Tasks were performed on a digital tablet which automatically extracted kinematic parameters including average pressure (AVP), maximum pressure (MXP), average speed (AVS), and average jerk (AVJ) across linguistic, cognitive non-linguistic, and non-cognitive non-linguistic tasks. A separate cohort comprising 16 patients with AD or mild cognitive impairment (MCI) and 16 matched controls was also evaluated.

RESULTS: Patients with OD-PACS showed significantly lower AVP, MXP, AVS, and AVJ values than HP (all p < 0.01), with deficits evident across all task categories. No significant correlations were found between olfactory test scores and kinematic parameters. In contrast, AD/MCI patients exhibited higher AVP and MXP in specific tasks.

CONCLUSIONS: This first kinematic handwriting analysis in OD-PACS reveals fine motor slowing, reduced pressure, and decreased movement variability. These alterations, independent of olfactory performance, may affect the reliability of handwriting-based AD screening in this population. Longitudinal studies are warranted to clarify causality and potential reversibility.},
}

@article {pmid41351874,
year = {2025},
author = {Stone, S and Keeney, T and Yildiz, F and Travis, A and Coglianese, E and Lewis, GD and Greer, JA and Steinhauser, K and Pastva, AM and Vranceanu, AM and Ritchie, CS},
title = {Understanding Patient and Care Partner Experiences With Rehabilitation After Hospitalization for Advanced Heart Failure: "I Was Thinking I'd Just Be Like I Was Before I Got This".},
journal = {Physical therapy},
volume = {},
number = {},
pages = {},
doi = {10.1093/ptj/pzaf144},
pmid = {41351874},
issn = {1538-6724},
abstract = {IMPORTANCE: Advanced Heart failure (HF) is a life-limiting condition that frequently necessitates hospitalization and subsequent post-acute rehabilitation for older adults. Despite high rates of post-acute care utilization, a notable gap exists in understanding the experiences of both patients and their care partners regarding rehabilitation.

OBJECTIVE: The objective was to conduct semi-structured interviews with older adults hospitalized with advanced HF and their care partners to explore their prior experiences with HF rehabilitation, including perceived benefits, unmet needs, and opportunities for improvement.

DESIGN: Between 2021 and 2023, a qualitative descriptive approach was used to conduct semi-structured interviews with patients hospitalized at an urban academic medical center with advanced HF (n = 12) and care partners (n = 11). Human-centered design principles and the Framework Method were used to guide study design and analyze semi-structured interviews.

SETTING: Recruitment took place in the inpatient setting of a large academic medical center. Qualitative interviews were conducted at bedside, in a quiet area in the hospital, or via Zoom after discharge. Interview location was guided by participant preferences and whether the patient had previously participated in HF rehabilitation prior to their current admission or was initiating rehabilitation for the first time following their hospitalization.

PARTICIPANTS: Patients were eligible to participate if they were community-dwelling (non-institutionalized), aged 65 years and older, had New York Heart Association (NYHA) Class III to IV symptoms, able to speak and read English, and had a history of receiving rehabilitation for their HF in the past (in any setting) or would be initiating it upon discharge. Patients were excluded if they were undergoing advanced therapy (organ transplant or left ventricular assist device placement), had severe cognitive impairment (diagnosis of Alzheimer's disease or related dementia, delirium, or altered mental status), or were enrolled in hospice during hospitalization or at hospital discharge.

RESULTS: Three deductive domains were characterized: (1) patient and care partner rehabilitation experiences, (2) facilitators and barriers to participating in rehabilitation, and (3) recommendations for optimizing rehabilitation. In the recommendations domain, several inductive themes emerged, including: (1) enhance rehabilitation structure, (2) optimize communication between patients and therapists, (3) incorporate symptom management, and (4) provide structured activity recommendations and goals.

RELEVANCE: Older adults with advanced HF are frequently hospitalized and require post-acute rehabilitation to address impairments in physical function. Our findings characterize patient and care partner experiences with post-acute rehabilitation and identify areas for improvement that may support the development of more effective post-acute rehabilitation interventions in advanced HF.},
}

@article {pmid41351718,
year = {2025},
author = {Krishnan, M and Kumaresan, M and Ravi, S and Martin, LC and Manikandan, B and Raman, T and Ramar, M},
title = {Bornyl Acetate and Menthol Provide Neuroprotection Against Lipopolysaccharide-Induced Alzheimer's Disease-Like Condition in C57BL/6 Mice by Downregulating NARC-1 Lipid Antagonist.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {262},
pmid = {41351718},
issn = {1559-1182},
mesh = {Animals ; *Alzheimer Disease/drug therapy/chemically induced/metabolism/pathology/prevention & control ; Mice, Inbred C57BL ; Lipopolysaccharides ; *Menthol/pharmacology/therapeutic use ; *Down-Regulation/drug effects ; Male ; *Neuroprotective Agents/pharmacology/therapeutic use ; Mice ; *Neuroprotection/drug effects ; Oxidative Stress/drug effects ; },
abstract = {Alzheimer's disease (AD) is a progressive neurological illness that causes Aβ deposition and cognitive impairments. Anti-cholinesterase and anti-depressant drugs are used as medications; however, their side effects spotlight the need for alternate treatments. Bornyl acetate and menthol are monoterpenes with bioactive potential investigated against inflammation induced by lipopolysaccharide (LPS) in C57BL/6 mice. In our study, we analysed various behavioural changes along with memory activities as well as assessed neuronal damage, acetylcholinesterase activity, amyloid deposition, mitochondrial membrane integrity, calcium deposition and oxidation derivatives. In addition, we also examined gene and protein expression associated with lipid dysfunction in neuroinflammation. Our findings revealed that monoterpenes such as bornyl acetate and menthol potentially improved LPS-induced behaviour changes and cognitive activities. In addition, these compounds have the potential effects against amyloid plaque formation, calcium build-up, mitochondrial membrane damage and oxidative markers (malondialdehyde, protein carbonyls and advanced glycation end products) in the LPS-injected C57BL/6 mice. Treatment with bornyl acetate and menthol also inhibited neural apoptosis-regulated convertase (NARC-1)/proprotein convertase subtilisin/kexin type 9 (PCSK-9) by upregulating low-density lipoprotein receptor-related protein (LRP)-1 protein expression. Cholesterol oxidation genes, including 11β-hydroxysteroid dehydrogenase 1 & 2, as well as proinflammatory microglial, apoptotic and amyloidogenic protein and gene expression, were decreased respectively when treated with monoterpenes while promoting the upregulation of anti-inflammatory. Based on the results, we concluded that these compounds can potentially target and prevent neuroinflammation, including Alzheimer's disease.},
}

Animals
*Alzheimer Disease/drug therapy/chemically induced/metabolism/pathology/prevention & control
Mice, Inbred C57BL
Lipopolysaccharides
*Menthol/pharmacology/therapeutic use
*Down-Regulation/drug effects
Male
*Neuroprotective Agents/pharmacology/therapeutic use
Mice
*Neuroprotection/drug effects
Oxidative Stress/drug effects

@article {pmid41351686,
year = {2025},
author = {Chen, M and Sheng, Z and Wang, L and Zhang, P and Zhang, J and Wang, X and Duan, J and Yang, W and , and Yu, W and Lü, Y},
title = {Leucine-Rich Repeat Kinase 2 Relates to Neuroaxonal Degeneration via Tau Pathology and Microglial Activation in Alzheimer's Disease.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {266},
pmid = {41351686},
issn = {1559-1182},
support = {CYYY-BSYJSCXXM-202334//The First Affiliated Hospital of Chongqing Medical University 2022 Chongqing Research Innovation Program for Graduate Student (CYB22199)/ ; CYYY-SSCX202524//First Affiliated Hospital of Chongqing Medical University 2025 Graduate Student Research Innovation Projects/ ; 0201【2022】No. 144 202325zdxk202105//Chongqing Medical Key Discipline and Regional Medical Key Discipline Development  Project 0201【2022】No. 144 202325/ ; CYB25212//Chongqing Graduate Student Research Innovation Project 2025/ ; No. 2021ZD0201802//grants from STI2030-Major Projects/ ; 2024NSCQ-LZX0020//Natural Science Foundation of Chongqing, China/ ; 2022YSZX-JSX0002CSTB//Science Innovation Programs Led by the Academicians in Chongqing under Project/ ; W0011//Program for Youth Innovation in Future Medicine, Chongqing Medical University/ ; W0166//Program for Youth Innovation in Future Medicine, Chongqing Medical University/ ; cstc2022ycjh-bgzxm0184//Chongqing Talent Plan/ ; KJZD-K202200405//Key Project of Science and Technology Research Program of Chongqing Municipal Education Commission/ ; },
mesh = {Humans ; *Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/metabolism/cerebrospinal fluid/genetics ; *Alzheimer Disease/pathology/genetics/metabolism ; *Microglia/pathology/metabolism ; Female ; Aged ; Male ; *tau Proteins/metabolism ; Middle Aged ; Biomarkers/cerebrospinal fluid ; *Nerve Degeneration/pathology ; },
abstract = {Leucine-rich repeat kinase 2 (LRRK2), a key contributor to Parkinson's disease (PD). However, its potential role in Alzheimer's disease (AD) progression remains unclear. This study analyzed baseline and 5-year follow-up data from 716 participants in the Alzheimer's Disease Neuroimaging Initiative (ADNI) and 87 participants in the Parkinson's Progression Markers Initiative (PPMI). Participants had cerebrospinal fluid (CSF) LRRK2 or LRRK2 (rs34637584 and rs76904798) genotypes, CSF biomarkers for AD core pathology, microglial activation and synaptic function, and underwent cognitive assessments. The mean age was 72.62 ± 7.34 years for the ADNI and 62.32 ± 9.66 years for the PPMI. The associations between LRRK2 and AD biomarkers were tested in CN, MCI and AD groups. In both ADNI and PPMI, CSF LRRK2 levels were correlated with CSF P-tau, T-tau, NfL, and α-syn. In ADNI, CSF LRRK2 showed correlations with sTREM2, PGRN, TREM2, TREML2, TRML1.ITIM, and Ng. Longitudinally, CSF LRRK2 was only correlated with the MOCA score in PPMI. Across CN, MCI, and AD groups, CSF LRRK2 levels exhibited correlations with sTREM2, PGRN, TREM2, TREML2, TREML1.ITIM, and NfL. The association between CSF LRRK2 and T-tau and P-tau was most pronounced in the MCI stage. Conversely, no significant association was observed between CSF LRRK2 and Aβ42 levels. Additionally, significant indirect effects were found in the TREM2-dependent mediation pathway in ADNI. This study suggests that CSF LRRK2 promotes tau-associated synaptic neurodegeneration, and TREM2-related microglial activation may play an important role.},
}

Humans
*Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/metabolism/cerebrospinal fluid/genetics
*Alzheimer Disease/pathology/genetics/metabolism
*Microglia/pathology/metabolism
Female
Aged
Male
*tau Proteins/metabolism
Middle Aged
Biomarkers/cerebrospinal fluid
*Nerve Degeneration/pathology

@article {pmid41351663,
year = {2025},
author = {Amirian, R and Merati, A and Babamohamadi, M and Mirahmadi, Y and Esfahani, ML and Rahmani, S and Izadi, Z and Rezazadeh, D},
title = {Navigating the Autophagy Maze: ATG and Their Impact on Neurodegenerative Diseases.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {260},
pmid = {41351663},
issn = {1559-1182},
mesh = {*Autophagy/genetics/physiology ; Humans ; *Neurodegenerative Diseases/genetics/metabolism/pathology ; Animals ; *Autophagy-Related Proteins/metabolism/genetics ; Signal Transduction ; },
abstract = {Autophagy, a tightly regulated process essential for maintaining cellular homeostasis, plays a critical role in the pathogenesis and progression of neurodegenerative diseases (NDs). These disorders-marked by diverse mechanisms and clinical heterogeneity-pose significant challenges in developing effective therapies. Central to the autophagic machinery are autophagy-related genes (ATGs), whose functions and variants are increasingly recognized as pivotal in modulating disease-specific pathways. This review explores the intricate roles of ATGs in NDs, emphasizing the need for a comprehensive understanding of molecular signaling networks, protein-protein interactions, and regulatory checkpoints that may serve as therapeutic targets. We highlight recent advancements in disease modeling, autophagy assays, and biomarker identification that facilitate the translation of ATG-related discoveries into clinical practice. Furthermore, we underscore the importance of interdisciplinary collaboration across academia, industry, clinical medicine, and regulatory bodies to harness the therapeutic potential of autophagy. This article aims to serve as a detailed roadmap for understanding the role of ATGs in NDs and to illuminate promising avenues for future research and therapeutic development.},
}

*Autophagy/genetics/physiology
Humans
*Neurodegenerative Diseases/genetics/metabolism/pathology
Animals
*Autophagy-Related Proteins/metabolism/genetics
Signal Transduction

@article {pmid41351658,
year = {2025},
author = {Singh, I and Singh, AK},
title = {Senolytics as Modulators of Critical Signaling Pathways: a Promising Strategy to Combat Brain Aging and Neurodegenerative Disorders.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {261},
pmid = {41351658},
issn = {1559-1182},
support = {CRG/2022/006612//Anusandhan National Research Foundation/ ; },
mesh = {Humans ; *Aging/drug effects/metabolism/pathology ; *Signal Transduction/drug effects ; *Neurodegenerative Diseases/drug therapy/metabolism/pathology ; *Brain/drug effects/metabolism/pathology ; Animals ; *Senotherapeutics/pharmacology/therapeutic use ; Oxidative Stress/drug effects ; },
abstract = {Aging of the brain, an intricate process, is a significant risk factor for neurodegenerative disorders (NDDs), such as Alzheimer's disease and Parkinson's disease. Senescent cell accumulation is an important hallmark of brain aging. These cells resist apoptotic cell death, produce proinflammatory cytokines, increase oxidative stress, and store toxic proteins that exacerbate neurodegeneration. These senescent cells cause neuroinflammation and dysfunction of the neuronal microenvironment by transmitting senescent phenotypes to neighboring healthy cells. Senolytics have become a viable treatment option to reduce the effects of brain aging since they specifically target and destroy senescent cells. Numerous senolytic compounds, such as dasatinib, fisetin, and quercetin, effectively eliminate senescent cells and reduce the accumulation of harmful substances, including misfolded toxic protein aggregates and reactive oxygen species, thereby helping to maintain tissue homeostasis. These medications aid in reducing oxidative stress and inflammation, two significant factors in brain aging and NDDs, by encouraging the removal of senescent cells. The key molecules involved in this process are mTOR, Nrf2-Keap1, AMPK, and Sirtuin 1 (SIRT1). The modulation of the mTOR and AMPK pathways affects autophagy and cellular metabolism, facilitating the elimination of harmful accumulations and damaged cell organelles. In addition, cellular repair and improved antioxidant defense are encouraged by the activation of the SIRT1 and Nrf2 pathways. The combination of senolytic therapy with these signaling pathways provides a novel approach to attack the cellular and molecular foundations of brain aging and neurodegenerative disorders.},
}

Humans
*Aging/drug effects/metabolism/pathology
*Signal Transduction/drug effects
*Neurodegenerative Diseases/drug therapy/metabolism/pathology
*Brain/drug effects/metabolism/pathology
Animals
*Senotherapeutics/pharmacology/therapeutic use
Oxidative Stress/drug effects

@article {pmid41351407,
year = {2025},
author = {Drozd, U and Vechkapova, S and Lanshakov, D},
title = {Pericytes in Brain Homeostasis: Developmental Roles and Adult Functions.},
journal = {Frontiers in bioscience (Landmark edition)},
volume = {30},
number = {11},
pages = {42742},
doi = {10.31083/FBL42742},
pmid = {41351407},
issn = {2768-6698},
support = {24-25-00154//Russian Science Foundation/ ; },
mesh = {Humans ; *Pericytes/physiology/metabolism/cytology ; *Homeostasis ; *Brain/growth & development/cytology/physiology/metabolism/embryology ; Animals ; Blood-Brain Barrier/metabolism ; Signal Transduction ; },
abstract = {Pericytes (PCs) are multifunctional mural cells embedded in the basement membrane of microvessels and play essential roles in the development and maintenance of the central nervous system. This review provides a comprehensive synthesis of the current knowledge on PC biology, tracing their trajectory from embryonic origins to specialized functions in the adult brain. During early brain development, PCs are recruited via platelet-derived growth factor B (PDGF-BB)/platelet-derived growth factor receptor beta (PDGFRβ) signaling and contribute to the formation of the blood-brain barrier (BBB), cortical architecture, and vascular stability. Their developmental plasticity is shaped by multiple embryonic origins and dynamic interactions with endothelial and neural precursor cells. In the adult central nervous system, PCs are central to maintaining BBB integrity, regulating cerebral blood flow, and modulating neurovascular coupling. They also participate in immune responses, metabolic waste clearance, and neuroprotection through the secretion of trophic factors and cytokines. Of particular interest is their emerging role in the expression of lipocalin-type prostaglandin D synthase (L-PGDS), which synthesizes prostaglandin D2-a molecule involved in sleep regulation, inflammation, and neurodegeneration. L-PGDS may also act as an amyloid β chaperone, implicating PCs in the pathology of Alzheimer's disease and other neurodegenerative disorders. The regulatory mechanisms of L-PGDS expression involve nuclear factor kappa B and Notch-Hes signaling, as well as potential modulation via brain-derived neurotrophic factor/tropomyosin receptor kinase B/protein kinase C pathway. By integrating developmental, molecular, and pathophysiological perspectives, this review positions PCs as key cellular regulators of brain function and highlights their potential as therapeutic targets in cerebrovascular and neurodegenerative diseases.},
}

Humans
*Pericytes/physiology/metabolism/cytology
*Homeostasis
*Brain/growth & development/cytology/physiology/metabolism/embryology
Animals
Blood-Brain Barrier/metabolism
Signal Transduction

@article {pmid41351381,
year = {2025},
author = {Beunders, AJM and Vijverberg, EGB and Teunissen, CE and Schouws, SNTM and Kupka, RW and Lemstra, AW and Dols, A},
title = {Patients With Older-Age Bipolar Disorder (OABD) Visiting a Memory Clinic: Differentiating Underlying Pathophysiology With MRI and Cerebrospinal Fluid Markers.},
journal = {Journal of geriatric psychiatry and neurology},
volume = {},
number = {},
pages = {8919887251407125},
doi = {10.1177/08919887251407125},
pmid = {41351381},
issn = {1552-5708},
abstract = {BackgroundMany patients with bipolar disorder (BD) report cognitive problems. Pathophysiology of cognitive impairment in BD is unclear, although prevalence of dementia in BD is high. In Older-Age Bipolar Disorder (OABD) patients with cognitive complaints, neurodegeneration may play a role. This could occur in at least 2 ways: (1) BD with 'comorbid' diagnosis of dementia; (2) specific neurobiological processes can underlie a cognitive impairment that is intrinsic of BD (ie, BD-related cognitive impairment).Methods102 OABD patients were selected from the Amsterdam Dementia Cohort study. Diagnostic workup included clinical and neuropsychological assessment, CSF biomarkers and MRI visual rating scales. About half of patients had depressive symptoms. We (1) examined which neurological diagnoses were identified by the memory clinic as the main cause of cognitive complaints. Subsequently, (2) in the remaining OABD patients with an unknown cause, we performed linear regression between biomarkers of neurodegeneration and composite cognitive score.Results29 OABD patients (28.4%) received a neurological diagnosis, 6 of which Alzheimer's Disease. In the remaining 73 (71.6%) OABD patients, a lower Aβ42 CSF concentration was related to lower composite cognitive scores (B = -0.143, P = 0.034), whereas CSF T-Tau, P-Tau, and MRI markers were not.ConclusionIn most OABD patients visiting a memory clinic, a neurological cause of cognitive complaints was not identified despite extensive diagnostic work-up. Altered amyloid metabolism may be an extra biological factor in the multifactorial puzzle that is BD-related cognitive impairment. Future studies should investigate a large range of biomarkers in relation to cognition in BD, including amyloid.},
}

@article {pmid41351181,
year = {2025},
author = {Wei, X and Li, L and Zhao, G and Luan, Y and Wang, Q and Ning, W},
title = {Hypertension and Alzheimer's disease: Pathological interplay, comorbidity risks, and new strategies for synergistic management.},
journal = {Clinical and experimental hypertension (New York, N.Y. : 1993)},
volume = {47},
number = {1},
pages = {2595154},
doi = {10.1080/10641963.2025.2595154},
pmid = {41351181},
issn = {1525-6006},
mesh = {Humans ; *Alzheimer Disease/epidemiology/prevention & control/physiopathology/therapy/pathology ; *Hypertension/epidemiology/therapy/physiopathology ; Risk Factors ; Antihypertensive Agents/therapeutic use ; Comorbidity ; },
abstract = {Hypertension and Alzheimer's disease (AD) are common comorbidities that seriously damage the health of the elderly. This review lays out the complex bidirectional association between hypertension and AD. From a pathological perspective, hypertension can not only indirectly increase the risk of AD through inducing cerebrovascular lesions such as atherosclerosis and stroke but also directly accelerate the core pathological progression of AD, including promoting the accumulation of amyloid-β (Aβ) proteins and the hyperphosphorylation of tau protein. Additionally, various shared modifiable risk factors, such as obesity, sleep disturbances, diet patterns, psychosocial factors etc., are summarized in detail, and their shared pathophysiological pathways, including chronic inflammation, oxidative stress and intestinal dysbiosis, are revealed. This article focuses on exploring the potential of synergistic management: on the one hand, some antihypertensive drugs, such as angiotensin II receptor blockers (ARBs), exhibit neuroprotective effects beyond blood pressure reduction. On the other hand, DASH, Mediterranean and MIND dietary patterns, along with regular physical exercise and positive psychological interventions, have all been proven to reduce the incidence risk of both diseases simultaneously. Digital health technology, such as the LETHE App provides a new paradigm for realizing dynamic monitoring and personalized management of risk factors. This review emphasizes that integrating hypertension prevention and control into the primary prevention strategy for AD and adopting a synergistic management plan that combines lifestyle interventions, medications, and digital technologies is crucial for achieving healthy aging.},
}

Humans
*Alzheimer Disease/epidemiology/prevention & control/physiopathology/therapy/pathology
*Hypertension/epidemiology/therapy/physiopathology
Risk Factors
Antihypertensive Agents/therapeutic use
Comorbidity

@article {pmid41350983,
year = {2025},
author = {Deng, H and Lee, TA and Gaber, CE and Kim, K and Crawford, SY and Bayliss, EA and Singh, S and Young, JG and Toh, S and Li, X},
title = {Treatment patterns of symptomatic treatments for Alzheimer's disease and related dementias.},
journal = {BMC geriatrics},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12877-025-06745-4},
pmid = {41350983},
issn = {1471-2318},
}

@article {pmid41350808,
year = {2025},
author = {Liang, H and Hunt, JB and Ma, C and Kovalenko, A and Calahatian, J and Pedersen, C and Liu, H and Li, J and Serrano, M and Blazier, D and Watler, M and Rocha-Rangel, P and Saunders, C and Blair, LJ and Breydo, L and Nash, K and Quadri, Z and Kraemer, B and Nelson, P and Norris, C and Abner, EL and Uversky, VN and Chaput, D and Selenica, MB and Lee, DC},
title = {Probing tau citrullination in Alzheimer's disease brains and mouse models of tauopathy.},
journal = {Acta neuropathologica},
volume = {150},
number = {1},
pages = {61},
pmid = {41350808},
issn = {1432-0533},
support = {AG084670/NH/NIH HHS/United States ; AG072728/NH/NIH HHS/United States ; },
mesh = {*Alzheimer Disease/metabolism/pathology ; *tau Proteins/metabolism ; Animals ; *Citrullination/physiology ; Mice ; *Brain/metabolism/pathology ; Disease Models, Animal ; Humans ; *Tauopathies/metabolism/pathology ; Mice, Transgenic ; Female ; Male ; Protein-Arginine Deiminase Type 2/metabolism ; },
abstract = {Alzheimer's disease (AD) includes a defining hallmark that correlates most closely to cognitive decline, namely misfolded tau protein. However, the "upstream" etiology and downstream clinical manifestations of tauopathies are quite diverse. Tau deposition elicits different pathological phenotypes and outcomes depending on the tau strain, proteoforms, and regional susceptibility. Posttranslational modifications (PTM) can alter tau structure, function, networks, and its pathological sequelae. We uncovered tau citrullination on multiple epitopes caused by peptidyl arginine deiminase (PAD) enzymes. PAD-induced citrullination irreversibly converts arginine residues to citrulline, producing a net loss of positive charge, elimination of pi-pi interactions, and increased hydrophobicity. We observed increased PAD2 and PAD4 in Alzheimer's disease (AD) brain and that they both can citrullinate tau. Tau can become citrullinated by PADs at all 14 arginine residues throughout the N-terminal domain (N-term), proline-rich domain (PR), microtubule-binding repeats domain (MBR), and C-terminal domain (C-term) on full-length tau (2N4R). Citrullination of tau impacts fibrillization and oligomerization rates in aggregation assays. Utilizing a panel of novel citrullinated tau (citR tau) antibodies, we identified citrullination of tau in vitro, several animal models of tauopathies, and Alzheimer's disease (AD). CitR tau increased with Braak stage and was enriched in AD brains with higher pathological tau burden. This work provides a new area of tau biology that signifies further consideration in the emerging spectrum of tauopathies and its clinical understanding.},
}

*Alzheimer Disease/metabolism/pathology
*tau Proteins/metabolism
Animals
*Citrullination/physiology
Mice
*Brain/metabolism/pathology
Disease Models, Animal
Humans
*Tauopathies/metabolism/pathology
Mice, Transgenic
Female
Male
Protein-Arginine Deiminase Type 2/metabolism

@article {pmid41350761,
year = {2025},
author = {He, H and Razlighi, QR and Gazes, Y and Habeck, C and Stern, Y and , },
title = {Integrating individualized connectome with amyloid pathology improves predictive modeling of future cognitive decline.},
journal = {Communications medicine},
volume = {5},
number = {1},
pages = {515},
pmid = {41350761},
issn = {2730-664X},
support = {R01 AG038465/AG/NIA NIH HHS/United States ; R01 AG026158/AG/NIA NIH HHS/United States ; },
abstract = {BACKGROUND: The deposition of amyloid-β (Aβ) in the human brain is a hallmark of Alzheimer's disease and is associated with cognitive decline. Aβ pathology is traditionally assessed at the whole-brain level across neocortical regions using positron emission tomography (PET). However, these measures often show weak associations with future cognitive impairment. A more sensitive pathology metric is needed to quantify early Aβ burden and better predict cognitive decline. Here, we aim to develop a network-based metric of Aβ burden to improve early prediction of cognitive decline in aging populations.

METHODS: We integrated subject-specific brain connectome information with Aβ-PET measures to construct a network-based metric of Aβ burden. Cross-validated predictive modeling was used to evaluate the performance of this metric in predicting longitudinal cognitive decline. Furthermore, we identified a neuropathological signature pattern linked to future cognitive decline, and we validated this pattern in an independent cohort.

RESULTS: Our results demonstrate that incorporating individualized structural connectome, but not functional connectome, information into Aβ measures enhances predictive performance for prospective cognitive decline. The identified neuropathological signature pattern is reproducible across cohorts.

CONCLUSION: These findings advance our understanding of the spatial patterns of Aβ pathology and its relationship to brain networks, highlighting the potential of connectome-informed network-based metrics for Aβ-PET imaging in identifying individuals at higher risk of cognitive decline.},
}

@article {pmid41350740,
year = {2025},
author = {Liu, X and Chen, J and Zhou, S and Lin, J},
title = {Genetic insights into drug targets for alzheimer's disease: integrative multi-omics analysis.},
journal = {Alzheimer's research & therapy},
volume = {17},
number = {1},
pages = {258},
pmid = {41350740},
issn = {1758-9193},
mesh = {Humans ; *Alzheimer Disease/genetics/drug therapy/cerebrospinal fluid ; Genome-Wide Association Study ; Mendelian Randomization Analysis ; Biomarkers/cerebrospinal fluid ; Proteomics ; Quantitative Trait Loci ; Amyloid beta-Peptides/cerebrospinal fluid ; Multiomics ; },
abstract = {BACKGROUND: The development of effective disease-modifying therapies for Alzheimer's disease (AD) remains a critical unmet need. While Mendelian randomization (MR) has been leveraged to identify genetic variants to accelerate AD target discovery, previous studies have been limited by narrow phenotypic coverage, insufficient multiomics validation, and inadequate mechanistic exploration. This study aims to overcome these limitations via comprehensive MR to identify robust therapeutic targets.

METHODS: We performed an integrative multiomics MR analysis leveraging over 50 genome-wide association study (GWAS) datasets spanning AD, cerebrospinal fluid (CSF) biomarkers (Aβ42, p-tau), neuroimaging endophenotypes, cognitive traits, and risk factors. Blood/CSF/brain protein quantitative trait loci (pQTLs) from large-scale proteomics studies were analyzed to identify druggable targets. A rigorous validation cascade was subsequently performed: Bayesian colocalization was performed to assess whether the same variants are associated with the protein and other traits; summary-data-based MR was performed to distinguish pleiotropy from linkage; mediation analysis was performed to quantify biomarker-driven causal pathways; integrated analysis of multiomics (single-cell RNA-seq and proteome) data was performed to resolve cellular specificity, and (PPI) interaction networks were generated; phenome-wide MR (Phe-MR) was performed across 679 traits to evaluate on-target side effects; and structure-based druggability screening was conducted.

RESULTS: Proteome-wide MR analysis revealed 15 potential drug targets for AD; six of these targets (PILRA, GRN, ACE, TIMD3, TREM2) were validated as Tier 1 (highest-confidence targets with external validation and causal consistency). Mediation analysis revealed that IDUA reduced the risk of AD through Aβ42 and p-tau in the CSF, whereas Siglec-7/9 increased the risk of AD through p-tau in the CSF. Additional targets revealed associations with AD biomarkers, neuroimaging, and cognitive function. Single-cell analysis highlighted the enrichment of key microglial and astrocyte targets. PPI network analysis revealed interaction pathways between seven drug targets and four AD therapeutics, and druggability assessment revealed seven potential therapeutics.

CONCLUSIONS: This study established a comprehensive AD target atlas, revealing mechanism-anchored targets that were validated across multiomics analyses and a clinically actionable framework integrating efficacy, biology, and safety profiling. Overall, these results advance AD drug discovery by revealing prioritized targets with causal biological support and providing a validated development roadmap.},
}

Humans
*Alzheimer Disease/genetics/drug therapy/cerebrospinal fluid
Genome-Wide Association Study
Mendelian Randomization Analysis
Biomarkers/cerebrospinal fluid
Proteomics
Quantitative Trait Loci
Amyloid beta-Peptides/cerebrospinal fluid
Multiomics

@article {pmid41350486,
year = {2025},
author = {Guo, Y and Cao, H and Zuo, C and Huang, Y and Gu, Z and Song, Y and Chen, X and Jiang, Q and Wang, F},
title = {Neuroprotective effects of SRS11-92 against oxidative stress-induced senescence via Nrf2/HO-1/NF-κB in Alzheimer's disease models.},
journal = {Inflammopharmacology},
volume = {},
number = {},
pages = {},
pmid = {41350486},
issn = {1568-5608},
support = {2020BCA089//National Key, Research and Development Program of Hubei Province/ ; 81974218//the National Natural Science Foundation of China/ ; },
abstract = {BACKGROUND: Oxidative stress, neuroinflammation, and cellular senescence interact to drive Alzheimer's disease (AD) progression. SRS11-92 is a redox-active small molecule with reported cytoprotective effects. This study sought to determine whether SRS11-92 mitigates Aβ-evoked oxidative stress and cellular senescence, and to delineate the underlying mechanism.

METHODS: SH-SY5Y cells were challenged with Aβ25-35 and pretreated with SRS11-92. Oxidative stress (ROS, MDA, SOD activity, and GSH), inflammatory mediators (TNF-α, IL-1β, and IL-6), senescence markers (SA-β-gal, p53, p16, and p21), and Nrf2/HO-1/NF-κB proteins were quantified. Pathway dependence was assessed using the selective Nrf2 inhibitor ML385. 3xTg-AD mice received SRS11-92 for 6 weeks; cognitive function was assessed by novel object recognition, cortical neuronal integrity was assessed by Nissl staining, and cellular senescence in the hippocampus was evaluated by SA-β-gal.

RESULTS: SRS11-92 attenuated Aβ25-35-induced cytotoxicity in a dose-dependent manner in SH-SY5Y cells, reduced ROS and MDA, and restored SOD activity and GSH. It suppressed TNF-α, IL-1β, and IL-6, decreased the percentage of SA-β-gal-positive cells, and downregulated p53, p16, and p21. Mechanistically, SRS11-92 increased total and nuclear Nrf2 and upregulated HO-1, while restricting NF-κB p65 nuclear translocation. ML385 abrogated these molecular and phenotypic benefits, confirming that SRS11-92 acts via the Nrf2 pathway in vitro. In 3xTg-AD mice, SRS11-92 improved cognitive function, partially rescued cortical Nissl-positive neurons, and reduced the hippocampal SA-β-gal-positive burden.

CONCLUSIONS: SRS11-92 exerts significant neuroprotective effects, attributable to reducing stress-induced senescence via activating Nrf2/HO-1 and constraining NF-κB signalling.},
}

@article {pmid41350438,
year = {2025},
author = {Liu, D and Li, X and Shi, P and Hong, W and Huang, J and Hou, M and Ma, L and Liao, Q and Yang, H and Fu, X and Zhou, H and Lu, J and Liu, Y and Feng, X and Wang, D and Zhou, R},
title = {7,8-Dihydroxyflavone ameliorates bone loss by regulating TRKB/AKT/FOXO3a pathway in a mouse model of alzheimer's disease.},
journal = {Psychopharmacology},
volume = {},
number = {},
pages = {},
pmid = {41350438},
issn = {1432-2072},
support = {81972112//National Natural Science Foundation of China/ ; },
abstract = {BACKGROUND: The incidence of osteoporosis is increased in Alzheimer's disease (AD). The pathogenesis of AD with osteoporosis is still unknown, there is no ideal treatment as yet for it. 7,8-Dihydroxyflavone (7,8-DHF), a functional brain-derived neurotrophic factor (BDNF) mimetic, shows therapeutic potential for neurological and orthopedic disorders.

OBJECTIVES: This research investigated the molecular mechanisms by which 7,8-DHF mitigates bone loss and cognitive dysfunction in osteoporotic AD mice.

METHODS: Micro-CT analysis quantified bone loss in AD mice. The Morris water maze (MWM) assessed mouse cognitive function, and immunohistochemical analysis measured Aβ plaque deposition. qPCR and Western blotting measured expression levels of APP, Aβ42, TRKB, and FOXO3a in osteoblasts isolated from femoral bone marrow mesenchymal stem cells (BMSCs) and brain tissue. ELISA determined the levels of IL-1β, IL-6, osteocalcin (OCN), fibroblast growth factor 23 (FGF23) and sclerostin. For in vitro experiments, osteoblast differentiation was monitored in MC3T3-E1 cells co-cultured with Aβ42, with concurrent measurement of TRKB, AKT, and FOXO3a expression. The efficacy of 7,8-DHF against bone loss and osteoblast differentiation was systematically evaluated.

RESULTS: Cognitive impairment and bone loss manifested in APP/PS1 mice. 7,8-DHF treatment ameliorated bone mass reduction, decreased Aβ42 expression in bone tissue, and enhanced TRKB expression. Concurrently, 7,8-DHF improved cognitive function and accelerated clearance of [¹²⁵I]-Aβ42 from the brain. In in-vitro, Aβ42 increased inflammatory cytokine levels, suppressed TRKB expression, and impaired osteoblast differentiation. 7,8-DHF reduced the levels of AKT and pFOXO3a by TRKB.

CONCLUSION: 7,8-DHF could alleviate bone mass loss in AD mice by regulating the TRKB/AKT/FOXO3a pathway. This finding provides new ideas for the treatment strategy of AD with osteoporosis and is beneficial to the health of the elderly.},
}

@article {pmid41350317,
year = {2025},
author = {Shetty, J and Shenoy, MK and Kolekar, SV and Prabhu, MM and Kotha, RR and Bhardwaj, S},
title = {Early detection of Alzheimer's disease progression: comparative evaluation of deep learning models.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {43242},
pmid = {41350317},
issn = {2045-2322},
mesh = {*Alzheimer Disease/diagnostic imaging/diagnosis/pathology ; Humans ; *Deep Learning ; Magnetic Resonance Imaging/methods ; Disease Progression ; Early Diagnosis ; Male ; Neuroimaging/methods ; Female ; Aged ; Brain/diagnostic imaging/pathology ; Neural Networks, Computer ; Biomarkers ; Image Processing, Computer-Assisted/methods ; },
abstract = {The accurate diagnosis and monitoring of Alzheimer's disease (AD) is particularly critical given the increasing number of cases worldwide. Improving forecasting precision using deep learning models on neuroimaging biomarkers can aid in more accurately predicting Alzheimer's associated disease progression. In this work, we assess two separate 3D Convolutional Neural Network (CNN) models for binary AD progression classification based on MRIs of the brain's structure. The first model uses a whole volume approach and processes entire MRI scans, thus requiring little computational power and minimal preprocessing compared to other methods. Alternatively, the second model applies voxel-level scrutiny by examining specific pre-defined brain regions that have statistically significant grey matter volume differences from cohort analyses. MRI preprocessing includes N4 bias field correction, segmentation of tissues, alignment to the Montreal Neurological Institute (MNI) space, and Gaussian smoothing for homogenization of image quality. For the region-focused model, feature extraction is driven by neuroanatomy, concentrating on areas where AD shows shrinkage changes. The full-volume CNN achieved a 94% validation accuracy, demonstrating high computational efficiency with its simpler architecture, while the region-guided model reached 95% accuracy by leveraging more complex domain-specific structural biomarkers, highlighting enhanced performance at the cost of increased model intricacy. This study highlights the potential of combining deep learning frameworks with neuroimaging biomarkers to improve early detection and monitoring of AD. While our findings highlight the value of guided feature selection and volumetric data evaluation in improving diagnostic precision, they are derived solely from the ADNI dataset and must be validated on more diverse clinical populations.},
}

*Alzheimer Disease/diagnostic imaging/diagnosis/pathology
Humans
*Deep Learning
Magnetic Resonance Imaging/methods
Disease Progression
Early Diagnosis
Male
Neuroimaging/methods
Female
Aged
Brain/diagnostic imaging/pathology
Neural Networks, Computer
Biomarkers
Image Processing, Computer-Assisted/methods

@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