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

@article {pmid41346709,
year = {2026},
author = {Liu, S and Semyachkina-Glushkovskaya, O and Yu, T and Ilukov, E and Rafailov, E and Sokolovski, S and Kurths, J and Zhu, D},
title = {Neuro-lymphaphotonics opens new horizons of the future technologies for the therapy of brain diseases.},
journal = {Theranostics},
volume = {16},
number = {2},
pages = {776-793},
pmid = {41346709},
issn = {1838-7640},
mesh = {Humans ; *Brain Diseases/therapy ; Animals ; Brain ; *Low-Level Light Therapy/methods ; *Lymphatic Vessels/radiation effects ; Blood-Brain Barrier ; },
abstract = {Pharmacological treatment of brain diseases is hampered by the blood-brain barrier that prevents the vast majority of drugs from entering the brain. For this reason, the pharmaceutical industry is reluctant to invest in the development of new neurotropic drugs. Even if effective pharmacological strategies for the treatment of brain diseases will be found, it will take 10-15 years between the emergence of an idea and the introduction of a drug to the market. This creates priority for the development of neuro-lymphaphotonics based on the development of promising non-pharmacological strategies for managing functions of the meningeal lymphatic vessels (MLVs). MLVs play a crucial role in the removal of toxins and metabolites from brain as well as in regulation of brain homeostasis and its immunity. Since MLVs are located on the brain surface, light penetrating the skull easily reaches MLVs and affects their functions. Therefore, MLVs are an ideal target for photobiomodulation (PBM). The pioneering studies have shown that PBM of MLVs is a promising strategy for the treatment of a wide range of neuropathology, including Alzheimer's or age-related brain diseases, brain tumor, intracranial hemorrhage, brain damages caused by diabetes. It has recently been discovered that sleep enhances the therapeutic effects of PBM and is a "therapeutic window" in overcoming the limitations of PBM in the elderly. Considering that the PBM technologies are non-invasive and safe with commercially viable possibilities (portability and low cost), neuro-lymphaphotonics open up promising prospects for the development of future technologies for the effective therapy of brain diseases.},
}

Humans
*Brain Diseases/therapy
Animals
Brain
*Low-Level Light Therapy/methods
*Lymphatic Vessels/radiation effects
Blood-Brain Barrier

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

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

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

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

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

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

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

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

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

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

TRIAL REGISTRATION: DRKS00031944.},
}

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

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

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

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

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

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

Humans
*Theranostic Nanomedicine/methods
Animals

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

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

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

@article {pmid41339994,
year = {2025},
author = {Sivalingam, AM and Sureshkumar, DD},
title = {The Central Role of m6A as Epigenetic Regulator in Metabolic Disorders of Therapeutic Potential and Clinical Implications.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {247},
pmid = {41339994},
issn = {1559-1182},
mesh = {Humans ; *Epigenesis, Genetic ; *Metabolic Diseases/genetics/therapy/metabolism ; *Adenosine/analogs & derivatives/metabolism/genetics ; Animals ; Aging/genetics ; },
abstract = {N6-methyladenosine (m6A) is the most common reversible mRNA modification, regulating fundamental cellular processes. It plays a vital role in aging and age-related diseases by influencing gene expression, RNA splicing, and stability. Growing evidence suggests that m6A modifications orchestrate key hallmarks of aging, including cellular senescence, stem cell exhaustion, and chronic inflammation factors that contribute to neurodegeneration, cardiovascular disease, and cancer. The intricate crosstalk between m6A and chromatin modifications is now recognized as a fundamental mechanism shaping age-associated epigenetic landscapes and influencing disease susceptibility. Core m6A regulators, such as METTL3, FTO, and ALKBH5, are implicated in age-related metabolic decline, neurodegeneration, and impaired tissue regeneration, making them promising therapeutic targets. Dysregulated m6A patterns are linked to aberrant RNA metabolism, protein aggregation, and synaptic dysfunction in Alzheimer's and Parkinson's diseases, while in cardiovascular and metabolic disorders, m6A modifications contribute to endothelial dysfunction, inflammation, and oxidative stress. Recent breakthroughs in computational modeling and RNA-editing technologies have revolutionized m6A research. High-precision deep-learning models (e.g., m6A-DCR) and CRISPR-based m6A editing tools provide powerful platforms to decode m6A's role in aging and disease progression. These advances pave the way for novel therapeutic strategies, offering opportunities for early diagnostics, precision medicine, and personalized interventions. Despite these promising developments, challenges remain in translating m6A-targeted therapies into clinical applications. Future research must enhance treatment specificity, minimize off-target effects, and elucidate the broader implications of m6A in aging. Advancing our understanding of m6A's functional landscape is essential for developing next-generation RNA-based therapeutics to combat aging and its associated diseases.},
}

Humans
*Epigenesis, Genetic
*Metabolic Diseases/genetics/therapy/metabolism
*Adenosine/analogs & derivatives/metabolism/genetics
Animals
Aging/genetics

@article {pmid41338979,
year = {2025},
author = {Nakamura, K and Kanou, M and Ito, S and Jimbo, T and Kouzaki, K and Nakazato, K and Nakamjima, R and Yamanouchi, K and Ueda, H and Yamana, K},
title = {Beta-nicotinamide mononucleotide attenuates creatine kinase release in Duchenne muscular dystrophy model rats.},
journal = {The Journal of veterinary medical science},
volume = {},
number = {},
pages = {},
doi = {10.1292/jvms.25-0258},
pmid = {41338979},
issn = {1347-7439},
abstract = {Beta-nicotinamide mononucleotide (beta-NMN) is a direct precursor of nicotinamide adenine dinucleotide (NAD[+]), a coenzyme essential for maintaining homeostasis in living organisms. NMN administration has attracted attention as a potential treatment for aging and age-related conditions, including diabetes, Alzheimer's disease, and chronic kidney disease. Duchenne muscular dystrophy (DMD) is a progressive, degenerative muscle disease caused by X-linked frameshift mutations in the Dmd gene. NAD[+] levels in skeletal muscle decline in DMD pathology. In this study, we explored the therapeutic potential of NMN as an NAD[+] booster for muscular dystrophy by administering NMN to DMD rats, which exhibit severe phenotypes comparable to those of human DMD patients, for 2 months. Although NMN administration did not improve muscle function in DMD rats, it did reduce the release of creatine kinase in their blood. RNA-seq analysis revealed that NMN administration could reverse DMD-related gene expression changes associated with skeletal muscle homeostasis. These results suggest that NMN can protect skeletal muscle against degeneration in DMD and may hold therapeutic potential for DMD patients.},
}

@article {pmid41338440,
year = {2025},
author = {Zarei, O and Talebi Moghadam, M and Vastegani, SM},
title = {Machine Learning and Deep Learning in Clinical Practice: Advancing Neurodegenerative Disease Diagnosis with Multimodal Markers.},
journal = {Brain research bulletin},
volume = {},
number = {},
pages = {111667},
doi = {10.1016/j.brainresbull.2025.111667},
pmid = {41338440},
issn = {1873-2747},
abstract = {Neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and multiple sclerosis, present major global health challenges due to their progressive and incurable nature. Early and accurate diagnosis is critical to slow disease progression and optimize therapeutic interventions, yet conventional diagnostic approaches-such as neuroimaging, cerebrospinal fluid biomarker analysis, and clinical evaluation-are often inadequate at the prodromal stage. Recent advances in artificial intelligence, particularly machine learning (ML), have provided new opportunities for precision diagnosis and treatment in neurology, using large data and multimodal biomarkers. Applications of ML to data from neuroimaging, electrophysiology, behavioral functions, speech and handwriting analysis, and molecular biomarkers have shown promising improvements in diagnostic accuracy, patient classification, and therapeutic recommendations. However, significant challenges remain, including data heterogeneity, model interpretability, population diversity, and ethical concerns surrounding patients' privacy. The purpose of this review is to examine current applications of ML in the diagnosis and management of neurodegenerative diseases through various data, highlight its strengths and limitations, and discuss future directions for using these approaches in clinical practice. We also outline emerging directions, including multimodal fusion with longitudinal data, federated and privacy-preserving learning, and the potential of explainable AI (XAI) and large language models (LLMs) in clinical decision support.},
}

@article {pmid41341247,
year = {2024},
author = {Lefkovitz, I and Walsh, S and Blank, LJ and Jetté, N and Kummer, BR},
title = {Direct Clinical Applications of Natural Language Processing in Common Neurological Disorders: Scoping Review.},
journal = {JMIR neurotechnology},
volume = {3},
number = {},
pages = {e51822},
pmid = {41341247},
issn = {2817-092X},
abstract = {BACKGROUND: Natural language processing (NLP), a branch of artificial intelligence that analyzes unstructured language, is being increasingly used in health care. However, the extent to which NLP has been formally studied in neurological disorders remains unclear.

OBJECTIVE: We sought to characterize studies that applied NLP to the diagnosis, prediction, or treatment of common neurological disorders.

METHODS: This review followed the PRISMA-ScR (Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews) standards. The search was conducted using MEDLINE and Embase on May 11, 2022. Studies of NLP use in migraine, Parkinson disease, Alzheimer disease, stroke and transient ischemic attack, epilepsy, or multiple sclerosis were included. We excluded conference abstracts, review papers, as well as studies involving heterogeneous clinical populations or indirect clinical uses of NLP. Study characteristics were extracted and analyzed using descriptive statistics. We did not aggregate measurements of performance in our review due to the high variability in study outcomes, which is the main limitation of the study.

RESULTS: In total, 916 studies were identified, of which 41 (4.5%) met all eligibility criteria and were included in the final review. Of the 41 included studies, the most frequently represented disorders were stroke and transient ischemic attack (n=20, 49%), followed by epilepsy (n=10, 24%), Alzheimer disease (n=6, 15%), and multiple sclerosis (n=5, 12%). We found no studies of NLP use in migraine or Parkinson disease that met our eligibility criteria. The main objective of NLP was diagnosis (n=20, 49%), followed by disease phenotyping (n=17, 41%), prognostication (n=9, 22%), and treatment (n=4, 10%). In total, 18 (44%) studies used only machine learning approaches, 6 (15%) used only rule-based methods, and 17 (41%) used both.

CONCLUSIONS: We found that NLP was most commonly applied for diagnosis, implying a potential role for NLP in augmenting diagnostic accuracy in settings with limited access to neurological expertise. We also found several gaps in neurological NLP research, with few to no studies addressing certain disorders, which may suggest additional areas of inquiry.

TRIAL REGISTRATION: Prospective Register of Systematic Reviews (PROSPERO) CRD42021228703; https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=228703.},
}

@article {pmid41338025,
year = {2025},
author = {Wagdy, M and Ibrahim, AA and Yahia, AM and Maher, RM and Abo-Elwafa, AH and Salah, A and Heikal, YM},
title = {Neurobiotech innovative strategies targeting Alzheimer's disease through therapeutic micro and macroalgae potentials.},
journal = {Journal of neuroimmunology},
volume = {411},
number = {},
pages = {578821},
doi = {10.1016/j.jneuroim.2025.578821},
pmid = {41338025},
issn = {1872-8421},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder identified by cognitive decline, memory loss, and behavioral changes, affecting approximately 50 million people worldwide. Genetic predisposition, environmental variables, and aging all play a role in the development of AD. Current therapeutic approaches primarily focus on alleviating symptoms through drugs such as donepezil and memantine. However, these treatments offer limited efficacy and may be accompanied by adverse effects. In contrast, natural therapies derived from algae present a promising alternative. Microalgae, including Chlorella and Spirulina, and macroalgae such as Fucus vesiculosus, Ecklonia cava, Sargassum, Laminaria japonica, and Fucus species, are rich in bioactive molecules having antioxidant and anti-inflammatory characteristics. These substances demonstrated potential in addressing the pathological features of AD, such as oxidative stress and neuroinflammation. Furthermore, advances in biotechnological tools like CRISPR-Cas9 gene editing are poised to enhance the efficacy of these natural therapies by targeting and modifying disease-associated genes. This review aims to bridge the fields of neurobiotechnology and marine bioresources by examining the synergistic potential of algal compounds and gene-editing strategies in combating Alzheimer's disease. Algal-derived compounds are utilized in pharmaceuticals, nutraceuticals, and dietary supplements, and may offer neuroprotective benefits that could aid in the prevention or treatment of AD.By integrating insights from molecular biology, pharmacology, and genomics, we seek to illuminate a novel, multidisciplinary framework for future therapeutic innovation.},
}

@article {pmid41338169,
year = {2025},
author = {Li, S and Li, X and Li, S and Chen, D and Xia, C},
title = {Discovery of novel hybrids of coumarin and quinoline as potential anti-Alzheimer's disease agent.},
journal = {Bioorganic & medicinal chemistry},
volume = {133},
number = {},
pages = {118499},
doi = {10.1016/j.bmc.2025.118499},
pmid = {41338169},
issn = {1464-3391},
abstract = {The multifaceted nature of Alzheimer's disease (AD) spurred growing interest in developing multi-target-directed ligands (MTDLs) for its prevention and treatment. Coumarin and quinoline scaffolds, recognized for their broad spectrum of AD-related biological activities including amyloid-β (Aβ) aggregation regulation, cholinesterase (ChE) inhibition, β-secretase 1 (BACE1) inhibition and neuroprotection, were identified as potential building blocks. Here in this study, 24 novel coumarin-quinoline hybrid compounds were rationally designed and synthesized. Inhibition studies targeting Aβ, ChE and BACE1 identified compound B8 as a promising lead compound. B8 exhibited effective binding to Aβ, and significantly attenuated Aβ-induced SH-SY5Y cell death by lowering oxidative stress and decreasing cellular apoptosis. Crucially, B8 demonstrated excellent blood-brain barrier (BBB) permeability, and intragastric administration of B8 to 7-month-old APP/PS1 transgenic mice resulted in improved cognitive function. This improvement was supported by the protection of hippocampal and cortical neurons from necrosis, attenuation of oxidative stress and inflammation in these brain regions, as well as a reduction in Aβ deposition. These findings highlight the potential of coumarin-quinoline hybrids as a novel class of AD therapeutics, with B8 emerging as a promising lead candidate warranting further investigation.},
}

@article {pmid41337426,
year = {2025},
author = {Li, J and Gao, Y and Yang, P and Guan, Z and Wang, T and Ma, G and Lei, B},
title = {Multi-Modal Feature Fusion Using Transformer for Early Alzheimer's Disease Diagnosis.},
journal = {Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual International Conference},
volume = {2025},
number = {},
pages = {1-4},
doi = {10.1109/EMBC58623.2025.11253151},
pmid = {41337426},
issn = {2694-0604},
mesh = {*Alzheimer Disease/diagnosis/diagnostic imaging ; Humans ; Deep Learning ; Algorithms ; Early Diagnosis ; },
abstract = {Alzheimer's disease (AD) is a common neurodegenerative disorder. Early and accurate diagnosis of AD is essential for effective treatment. However, due to the class imbalance problem, there is a significant data gap between different categories. Moreover,the data feature differences of AD are relatively small, which poses challenges for its application in the early diagnosis of AD. To tackle these problems, we propose an intelligent early AD diagnosis model based on Transformer. The deep learning diagnosis model utilizes Transformer to integrate image features and non-image features. Furthermore, it incorporates a class imbalance loss function to optimize the performance of early AD diagnosis, thereby enhancing the model's ability to recognize underrepresented classes. In order to alleviate the problem of class imbalance and test the model performance, we used stratified 5-fold cross validation to verify the model effect.Experimental results demonstrate that our model can significantly improve the accuracy of AD diagnosis, which is markedly better than traditional methods. Additionally, loss function we used more effectively mitigates the problem of class imbalance. We believe this work can effectively reduce the burden on medical staff to diagnose early AD.},
}

*Alzheimer Disease/diagnosis/diagnostic imaging
Humans
Deep Learning
Algorithms
Early Diagnosis

@article {pmid41337360,
year = {2025},
author = {Lee, HP and Arginteanu, T and Kudela, P and Wyse-Sookoo, K and Anderson, WS and Salimpour, Y},
title = {Phase-Dependent Neuromodulation in a Computational Hippocampal Model.},
journal = {Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual International Conference},
volume = {2025},
number = {},
pages = {1-4},
doi = {10.1109/EMBC58623.2025.11254724},
pmid = {41337360},
issn = {2694-0604},
mesh = {*Hippocampus/physiology ; Humans ; *Models, Neurological ; Computer Simulation ; Theta Rhythm/physiology ; Neurons/physiology ; Animals ; },
abstract = {The critical role of phase-amplitude coupling (PAC) between oscillations of differing frequencies highlights the promise of phase-dependent neuromodulation as a therapeutic strategy for various neurological conditions. In the hippocampus, theta-gamma PAC is linked to key memory processes and information transfer. Computational models avoid technical challenges in in vivo and in vitro experiments and offer a practical alternative for exploring the mechanisms behind phase-dependent effects. In this study, we built on a published CA3 hippocampal computational model implemented in the NEURON-Python environment. We used a closed-loop autoregressive (AR) forward prediction model that sampled the network's local field potential (LFP) to achieve real-time calculation of stimulus time points locked to a target phase of the theta oscillation. Our approach enabled the delivery of current injections to all neuronal populations at either the peak or the trough of the theta rhythm. Analysis of the resulting network LFP showed distinct phase-dependent changes in the theta band during stimulation. The peak-phase stimulation significantly enhanced theta-gamma coupling. Further study on a large-scale human-based model is needed to better capture these phase-dependent effects. Overall, the results underscored the importance of closed-loop stimulation systems and the potential of phase-targeted neuromodulation to influence PAC. These findings offer new avenues for treating disorders marked by disrupted oscillations, including Alzheimer's disease and other memory disorders.Clinical Relevance- This study provides investigations of the origins of neuronal oscillations and the development of a brain stimulation technique for modulating the level of oscillations, possibly contributing to the development of novel treatment methods for neurological disorders associated with abnormal oscillations..},
}

*Hippocampus/physiology
Humans
*Models, Neurological
Computer Simulation
Theta Rhythm/physiology
Neurons/physiology
Animals

@article {pmid41337282,
year = {2025},
author = {Uhm, J and Kim, HY and Choe, B and Agrawal, H and Yoon, S and Yun, JH},
title = {Smartphone Keystroke-based Cognitive Impairment Diagnostic Methodology.},
journal = {Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual International Conference},
volume = {2025},
number = {},
pages = {1-7},
doi = {10.1109/EMBC58623.2025.11253467},
pmid = {41337282},
issn = {2694-0604},
mesh = {Humans ; *Smartphone ; *Cognitive Dysfunction/diagnosis ; Male ; Aged ; Female ; },
abstract = {With the global population rapidly aging, dementia has emerged as a major public health concern. Significant efforts are being made to address the health and other problems associated with dementia. Although several advances have been made in the diagnosis and treatment of dementia, many challenges remain unresolved. Existing dementia diagnostic methods are often not performed in a timely manner due to poor accessibility, leading to delays in initiation of treatment. In this study, we propose a smartphone keystroke-based diagnostic method as a solution to overcome the limitations associated with the early diagnosis and treatment of dementia. As compared to other existing methods, the proposed diagnostic method is easier to develop and maintain, promoting commercialization and widespread use. The diagnostic method has been designed to extract language-agnostic keystroke data features from smartphone keyboard input logs. Rather than simply extracting features assessing motor skills from keystroke data or features demonstrating language usage patterns from text, this study focused on features that can assess cognitive abilities without using linguistic characteristics. Clinical trials were conducted in patients with mild cognitive impairment and early Alzheimer's dementia were conducted, and a series of experiments and validation tests were performed using the trial data. The results demonstrated that the proposed smartphone keystroke-based diagnostic method is effective in diagnosing cognitive impairment. The proposed method does not require the use of any special equipment except smartphones, which facilitates low-cost commercialization. This study presents a diagnostic method that addresses the problem of people who avoid tests for the diagnosis of dementia due to economic and psychological burdens.Clinical RelevanceThis study provides an approach for early detection of dementia using ordinary smartphone keystroke logs. The proposed method has the potential to improve the quality of life of patients with dementia. Following large-scale clinical research and the integration of more digital biomarkers, the methodology proposed in this study can potentially facilitate the development of an early diagnostic platform for dementia.},
}

Humans
*Smartphone
*Cognitive Dysfunction/diagnosis
Male
Aged
Female

@article {pmid41336985,
year = {2025},
author = {Salinas-Medina, A and Gonzalez-Mitjans, A and Toussaint, PJ and Liu, X and Evans, A},
title = {HISRON: AI-Driven GPU-Accelerated Framework for Scalable High-Resolution Neuroimaging Analysis.},
journal = {Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual International Conference},
volume = {2025},
number = {},
pages = {1-7},
doi = {10.1109/EMBC58623.2025.11253703},
pmid = {41336985},
issn = {2694-0604},
mesh = {Humans ; *Neuroimaging/methods ; *Image Processing, Computer-Assisted/methods ; *Computer Graphics ; Algorithms ; *Artificial Intelligence ; Brain/diagnostic imaging ; },
abstract = {Ultra-high-resolution imaging, particularly cellular neuroimaging, poses challenges from terabyte-scale data and computational complexity. We present HISRON (High-Resolution Scalable Neuroimaging) a GPU-accelerated framework enabling scalable multidimensional analysis, combining unsupervised learning for adaptive feature extraction, benchmarked anisotropic diffusion for noise reduction, and promptable segmentation models with a zero-shot generalization feature. Dynamic overlap-aware tiling maximizes parallelization while preserving spatial context, enabling real-time processing of complex structures. Built on NVIDIA CUDA and CuPy, the framework achieves transformative efficiency: 10x faster noise reduction and detection of 200,000 neuron centroids in 30 seconds (40% pipeline improvement). This advances integration with AI-driven segmentation/classification pipelines, overcoming bottlenecks in high-dimensional computer vision. By emphasizing scalability, our method accelerates analysis of biomedical imaging data, directly supporting translational healthcare innovations in neuroscience. The tool's adaptability underscores its potential for clinical research, enhancing precision in neuroanatomical studies and fostering discoveries in brain function and pathology.Clinical relevance-The proposed framework directly addresses critical challenges in modern clinical neuroimaging, where the analysis of high-resolution data is essential for diagnosing and monitoring neurological disorders such as Alzheimer's, Parkinson's diseases, and epilepsy. By enabling real-time processing of terabyte-scale datasets, this technology reduces delays in image interpretation, facilitating faster decision-making in time-sensitive scenarios, such as intraoperative imaging during neurosurgery or stroke assessment. The zero-shot segmentation model's adaptability ensures robust performance across heterogeneous imaging protocols, which is vital for multicenter clinical studies and personalized treatment planning. Additionally, the framework's efficiency in detecting neuron populations at scale supports large-scale neuroanatomical studies, enhancing our understanding of brain connectivity abnormalities in psychiatric and neurodegenerative conditions. By lowering computational barriers, this tool democratizes access to advanced imaging analytics, empowering clinics with limited resources to adopt precision medicine approaches. These advancements align with the growing demand for AI-driven scalable solutions to improve diagnostic accuracy, accelerate therapeutic discovery, and optimize patient outcomes in neurology and neurorehabilitation.},
}

Humans
*Neuroimaging/methods
*Image Processing, Computer-Assisted/methods
*Computer Graphics
Algorithms
*Artificial Intelligence
Brain/diagnostic imaging

@article {pmid41336397,
year = {2025},
author = {Seo, K and Hwang, J and Kim, K and Argrawal, H and Yun, JH and Yoon Kim, H},
title = {End-to-End Classification of Cognitive Impairment Using Daily-Life Gait Data.},
journal = {Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual International Conference},
volume = {2025},
number = {},
pages = {1-7},
doi = {10.1109/EMBC58623.2025.11254035},
pmid = {41336397},
issn = {2694-0604},
mesh = {Humans ; *Cognitive Dysfunction/diagnosis/physiopathology/classification ; *Gait ; Aged ; Male ; Female ; Middle Aged ; Smartphone ; Accelerometry ; *Activities of Daily Living ; Alzheimer Disease/diagnosis/physiopathology ; Wearable Electronic Devices ; },
abstract = {We investigated the feasibility of using commercial smart devices to prescreen cognitive impairments for timely intervention. A total of 125 individuals aged 50 and older were recruited from a local clinic and categorized into groups based on cognitive diagnosis: Mild Alzheimer's Disease (AD), Mild Cognitive Impairment (MCI), and Subjective Cognitive Decline (SCD).This study focused on distinguishing individuals requiring treatment (AD and MCI) from those without cognitive impairment (SCD) using gait-related data collected from daily life. This classification task was particularly challenging, as the SCD group shares cognitive symptoms with MCI and the data was collected in non-controlled, real-world conditions.Participants used smartphones and smartwatches for one month to collect accelerometer and gyroscope data during daily activities. We preprocessed walking segments and trained a deep learning classifier to differentiate between the two groups. The model achieved an area under the curve (AUC) of 0.70, demonstrating the potential of wearable-based gait analysis for cognitive impairment detection. A sensor ablation study revealed that wrist-worn gyroscope data alone achieved a comparable AUC of 0.70, suggesting a moderate association between arm motion and cognitive impairment. The results further indicated that integrating smartphone accelerometers and smartwatch gyroscopes enhanced classification performance.This study is part of a broader multimodal research initiative that integrates gait analysis with voice recordings, phone usage patterns, and other behavioral data to improve cognitive impairment classification. Future work will explore multi-modal fusion techniques to enhance accuracy and reliability, with the long-term goal of developing accessible, real-world screening tools for early detection.},
}

Humans
*Cognitive Dysfunction/diagnosis/physiopathology/classification
*Gait
Aged
Male
Female
Middle Aged
Smartphone
Accelerometry
*Activities of Daily Living
Alzheimer Disease/diagnosis/physiopathology
Wearable Electronic Devices

@article {pmid41336106,
year = {2025},
author = {Shanmugasundaram, S and K, GG and Sinha, N},
title = {EEG Complexity Measures for Alzheimer's and Frontotemporal Dementia Classification Using Explainable Machine Learning.},
journal = {Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual International Conference},
volume = {2025},
number = {},
pages = {1-7},
doi = {10.1109/EMBC58623.2025.11253046},
pmid = {41336106},
issn = {2694-0604},
mesh = {Humans ; *Alzheimer Disease/diagnosis/physiopathology/classification ; *Electroencephalography/methods ; *Frontotemporal Dementia/diagnosis/physiopathology/classification ; *Machine Learning ; Male ; Female ; Aged ; Signal Processing, Computer-Assisted ; Middle Aged ; },
abstract = {This study aimed to classify patients with Alzheimer's disease (AD) and frontotemporal dementia (FTD) from healthy controls (CN) using non-linear EEG features. We explored various classification tasks, including binary classifications (CN vs. AD, CN vs. FTD, FTD vs. AD) and multi-class classifications, employing machine learning models such as XGBoost, multi-layer perceptron, k-nearest neighbors, and support vector machines. To understand the model's decision-making process, we employed explainable AI (XAI) using SHAP (SHapley Additive exPlanations) analysis. An EEG dataset of 88 subjects: 36 with AD, 29 controls, and 23 with FTD, was used. The occipital electrode O2 played a crucial role in differentiating AD from controls. In both FTD vs. AD and CN vs. FTD classifications, features from the frontal and temporal electrodes exhibited the highest importance. The results showed that XGB and MLP perform best across all classification tasks, with 100% accuracy achieved in CN vs. AD classification and area under the curve values of 0.99 for most classifiers. Distinguishing unhealthy patients (AD and FTD) from healthy controls yielded lower performance, potentially due to the differential EEG signal alterations in these conditions. The multi-class classification of AD, FTD, and controls achieved accuracy of 82%, lower than the binary classification tasks. The study proposed a novel methodology combining non-linear EEG features and machine learning models, offering the potential for improved disease detection.Clinical relevance- This study offers the potential to provide a non-invasive, efficient method for early detection and differentiation of AD and FTD from healthy controls. The ability to classify these neurodegenerative diseases using EEG, a widely accessible and cost-effective tool, could significantly aid in the timely diagnosis and monitoring of disease progression. This could lead to more personalized treatment plans and improved patient care.},
}

Humans
*Alzheimer Disease/diagnosis/physiopathology/classification
*Electroencephalography/methods
*Frontotemporal Dementia/diagnosis/physiopathology/classification
*Machine Learning
Male
Female
Aged
Signal Processing, Computer-Assisted
Middle Aged

@article {pmid41335145,
year = {2025},
author = {Banu, Z and Das, NR},
title = {Protective effects of alkaloidal fraction of Elaeocarpus angustifolius Blume against AlCl3-evoked neurotoxicity: insights from an in vivo model of Alzheimer's disease.},
journal = {Metabolic brain disease},
volume = {40},
number = {8},
pages = {330},
pmid = {41335145},
issn = {1573-7365},
mesh = {Animals ; *Alzheimer Disease/drug therapy/chemically induced/metabolism/pathology ; Aluminum Chloride/toxicity ; *Neuroprotective Agents/pharmacology/therapeutic use ; Rats ; Male ; *Plant Extracts/pharmacology/therapeutic use ; Disease Models, Animal ; *Alkaloids/pharmacology/therapeutic use ; Hippocampus/drug effects/metabolism/pathology ; Oxidative Stress/drug effects ; Maze Learning/drug effects ; Amyloid beta-Peptides/metabolism ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, memory loss, and neuronal degeneration. Current treatments offer limited efficacy. Elaeocarpus angustifolius Blume (Rudraksha), used traditionally in Ayurveda for neurological disorders, has shown potential for cognitive health, warranting investigation in AD models. This study aimed to evaluate the neuroprotective efficacy of an alkaloid-rich fraction of E. angustifolius (EAF) in an AlCl3-induced rat model of AD. AD-like symptoms were induced by oral administration of AlCl3 (100 mg/kg) for 60 days, followed by a 30-day oral treatment with EAF (200 and 400 mg/kg). Cognitive performance was assessed using the Morris water maze, elevated plus maze, novel object recognition, and locomotor activity tests. Biochemical and molecular markers were analysed, and hippocampal histopathology was conducted. AlCl3 exposure caused significant cognitive and motor deficits, elevated Aβ1-42 and phosphorylated tau, decreased acetylcholine and dopamine, increased glutamate and NF-κB, and reduced NRF-2 expression, indicating oxidative stress and neuroinflammation. EAF treatment significantly improved behavioral outcomes, reduced Aβ1-42 and tau levels, restored neurotransmitter balance, enhanced antioxidant markers (GSH, SOD, CAT), and reduced MDA. It suppressed NF-κB and upregulated NRF-2, suggesting antioxidant and anti-inflammatory effects. Histopathological analysis confirmed hippocampal neuroprotection. EAF exhibited significant neuroprotective effects by mitigating oxidative stress, neuroinflammation, and AD-related pathologies, including amyloid accumulation and cholinergic dysfunction. These findings support the potential of EAF as a therapeutic candidate for AD prevention and management.},
}

Animals
*Alzheimer Disease/drug therapy/chemically induced/metabolism/pathology
Aluminum Chloride/toxicity
*Neuroprotective Agents/pharmacology/therapeutic use
Rats
Male
*Plant Extracts/pharmacology/therapeutic use
Disease Models, Animal
*Alkaloids/pharmacology/therapeutic use
Hippocampus/drug effects/metabolism/pathology
Oxidative Stress/drug effects
Maze Learning/drug effects
Amyloid beta-Peptides/metabolism

@article {pmid41333818,
year = {2025},
author = {An, L and Zhang, J and Wang, X and Ge, Y and Sun, K and Dong, J and Wang, P and Li, W and Li, M and Hu, X and Wang, B and Yu, XA},
title = {Nanocarriers based therapy and diagnosis of brain diseases: cross the blood-brain barrier.},
journal = {Science and technology of advanced materials},
volume = {26},
number = {1},
pages = {2554048},
pmid = {41333818},
issn = {1468-6996},
abstract = {The blood-brain barrier (BBB) is the protective interface that isolates the central nervous system from circulating blood, which restricts approximately 98% of small molecule drugs and nearly all large molecules from entering the brain. Current methods to bypass the BBB, such as laser-guided interstitial thermal therapy and magnetic resonance guided focused ultrasound, are fraught with risks like impairing BBB integrity and brain damage, and are not suitable for long-term treatment. Nanocarriers have emerged as promising tools due to their ability to enhance drug delivery across the BBB while minimizing systemic toxicity. These nanocarriers leverage mechanisms including receptor-mediated, carrier-mediated, cell mediated and extra-stimuli mediated transport to improve BBB traverse and brain targeting. The review evaluates these strategies separately, discussing their potential and limitations for clinical application, and highlights recent advancements in integrating and optimizing nanocarriers utilizing synergistic strategies for the treatment and diagnosis of neurological disorders, including tumors, Alzheimer's disease, Parkinson's disease, and brain infections.},
}

@article {pmid41332987,
year = {2025},
author = {Huai, JX and Chang, EE and Zhu, YR and Ma, WL and Lv, TS and Sun, J and Zhou, XQ},
title = {Diabetic encephalopathy: metabolic reprogramming as a potential driver of accelerated brain aging and cognitive decline.},
journal = {Frontiers in cell and developmental biology},
volume = {13},
number = {},
pages = {1701406},
pmid = {41332987},
issn = {2296-634X},
abstract = {Diabetic encephalopathy (DE) is a serious neurological complication of diabetes and is expressed as progressive decline in cognitive function, emotional disorders, and changes in brain structure. This review brings together the relevant evidence and demonstrates that metabolic reprogramming, the adaptive reconfiguration of the core metabolic pathway in response to hyperglycemia, is a potential driver of accelerated brain aging in DE. The main pathological characteristics are: abnormal brain insulin signaling, resulting in a decrease in neuronal glucose intake and a decrease in mitochondrial oxidative phosphorylation, oxidative stress and neuroinflammation caused by high blood sugar, in which excess reactive oxygen species (ROS), impairs mitochondrial integrity and leads to activation of microglia cells. The impaired mitophagy and the macrophages remove defects and cause the accumulation and energy collapse of the dysfunctional organelles. In addition, it promotes excessive glycolytic flux, lipolysis disorder, lactic acid accumulation, and ceramide-dependent synaptic damage. We further examine shared metabolic mechanisms between DE and neurodegenerative diseases such as alzheimer's disease (AD) and treatment strategies for pathological metabolic reprogramming including GLP-1 receptor agonists, NAD[+] boosters, and AMPK activators. This analysis laid the foundation for new intervention measures against the development of DE.},
}

@article {pmid41332414,
year = {2025},
author = {Zhao, X and Xu, Z and Wang, D and Li, T and Xu, L and Li, Z and Bai, X and Zhu, H and Liu, Y and Wang, Y},
title = {Nanotechnology-based targeted regulation of NLRP3 Inflammasome: therapeutic strategies and clinical application prospects in inflammatory diseases.},
journal = {Drug delivery},
volume = {32},
number = {1},
pages = {2580730},
doi = {10.1080/10717544.2025.2580730},
pmid = {41332414},
issn = {1521-0464},
mesh = {*NLR Family, Pyrin Domain-Containing 3 Protein/metabolism/antagonists & inhibitors ; Humans ; *Inflammasomes/metabolism ; Animals ; *Inflammation/drug therapy/metabolism ; Drug Delivery Systems/methods ; Nanotechnology/methods ; *Anti-Inflammatory Agents/administration & dosage/pharmacology ; Reactive Oxygen Species/metabolism ; Nanoparticles ; Nanomedicine/methods ; },
abstract = {The NLRP3 inflammasome plays a critical role in the onset and progression of various inflammatory diseases, making targeting its activation an important research direction for treating these conditions. Nanotechnology can effectively inhibit the activation of the NLRP3 inflammasome through several mechanisms, such as scavenging reactive oxygen species (ROS), regulating calcium ion flux, and stabilizing mitochondrial function, thereby alleviating inflammation and promoting tissue repair. Studies have demonstrated that nanomaterials exhibit promising anti-inflammatory effects in animal models, showing broad application potential, particularly in the treatment of conditions such as atherosclerosis, diabetes, and Alzheimer's disease. However, the clinical translation of nanotherapy still faces numerous challenges, including issues related to material biocompatibility, long-term safety, targeting efficiency, and controlled drug delivery. Future research should integrate targeting ligands, responsive materials, and multifunctional nanoplatforms to enhance the specificity and efficacy of treatments while minimizing side effects. Additionally, the prospects of nanotechnology in personalized treatment and clinical applications are substantial, necessitating further integration of basic research with clinical validation to expedite the clinical translation of NLRP3-targeted nanomedicines.},
}

*NLR Family, Pyrin Domain-Containing 3 Protein/metabolism/antagonists & inhibitors
Humans
*Inflammasomes/metabolism
Animals
*Inflammation/drug therapy/metabolism
Drug Delivery Systems/methods
Nanotechnology/methods
*Anti-Inflammatory Agents/administration & dosage/pharmacology
Reactive Oxygen Species/metabolism
Nanoparticles
Nanomedicine/methods

@article {pmid41331838,
year = {2025},
author = {Kumar, N and Jangid, K and Kumar, V and Devi, B and Arora, T and Mishra, J and Kumar, V and Dwivedi, AR and Parkash, J and Bhatti, JS and Kumar, V},
title = {Investigations of 3-Hydroxy Chromone Derivatives as Multipotent Therapeutics for the Treatment of Alzheimer's Disease: In Silico and In Vitro Interventions and Fluorescence Studies.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.5c00847},
pmid = {41331838},
issn = {1948-7193},
abstract = {Chromone-based small organic molecules are designed and synthesized as putative multipotent ligands to intervene in several interlinked pathological pathways of Alzheimer's disease. The synthesized compounds were evaluated as acetylcholinesterase, monoamine oxidase, and amyloid β aggregation inhibitors using biochemical assays. Most of the compounds were found to inhibit the enzymes in a lower micromolar concentration range. In the series, two compounds, i.e., NSS-16 and NSS-18, displayed a balanced activity profile with the IC50 values of 1.77 and 1.53 μM against AChE and 2.06 and 1.51 μM against MAO-B. NSS-16 and NSS-18 showed moderate inhibitory activity against the self-induced Aβ aggregation with inhibition percentages of 17.8 and 24.0%, respectively. These compounds also showed potent antioxidant activity and formed metal chelates. In addition, the compounds were tested against SH-SY5Y neuronal cells and found to be neuroprotective and noncytotoxic. Moreover, the compounds inhibited reactive oxygen species (ROS) production up to 70% and exhibited a mixed type of inhibition in enzyme kinetic studies of AChE. These chromone derivatives showed a strong fluorescence intensity with a quantum yield of 30-50% and can be utilized in various biological studies including in vitro and in vivo assessments. Computational studies showed that the lead compounds fit well in the active cavity of enzymes and displayed thermodynamic stability for a time interval of 100 ns. Thus, these compounds displayed a multipotent activity profile and have the potential to be developed as potential therapeutics for AD.},
}

@article {pmid41330788,
year = {2025},
author = {Zimmer, JA and Sims, JR and Evans, CD and Nery, ESM and Wang, H and Wessels, AM and Tronchin, G and Sato, S and Raket, LL and Andersen, SW and Sapin, C and Paget, MA and Gueorguieva, I and Ardayfio, P and Khanna, R and Brooks, DA and Matthews, BR and Mintun, MA and , },
title = {Donanemab in early symptomatic Alzheimer's disease: results from the TRAILBLAZER-ALZ 2 long-term extension.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {},
number = {},
pages = {100446},
doi = {10.1016/j.tjpad.2025.100446},
pmid = {41330788},
issn = {2426-0266},
abstract = {BACKGROUND: Donanemab significantly slowed clinical progression in participants with early symptomatic Alzheimer's disease (AD) during the 76-week placebo-controlled period of TRAILBLAZER-ALZ 2.

METHODS: Participants who completed the placebo-controlled period were eligible for the 78-week, double-blind, long-term extension (LTE). Early-start participants were randomized to donanemab in the placebo-controlled period. Delayed-start participants (randomized to placebo) started donanemab in the LTE. Participants who met amyloid treatment course completion criteria were switched to placebo. An external control cohort comprised participants from the AD Neuroimaging Initiative (ADNI).

RESULTS: At 3 years, donanemab slowed disease progression on the Clinical Dementia Rating Scale (CDR)-Sum of Boxes (CDR-SB) in early-start participants versus a weighted ADNI control (-1.2 points; 95 % confidence interval [CI], -1.7, -0.7). Seventy-six weeks after initiating donanemab, delayed-start participants also demonstrated slower CDR-SB progression versus a weighted ADNI control (-0.8 points; 95 % CI, -1.3, -0.3). Participants who completed treatment by 52 weeks demonstrated similar slowing of CDR-SB progression at 3 years. Compared with delayed-start participants, early-start participants demonstrated a significantly lower risk of disease progression on the CDR-Global over 3 years (hazard ratio=0.73; p < 0.001). In both groups, >75 % of participants assessed by positron emission tomography 76 weeks after starting donanemab achieved amyloid clearance (<24.1 Centiloids). The addition of LTE data to prior modeling predicted a median reaccumulation rate of 2.4 Centiloids/year. No new safety signals were observed compared to the established donanemab safety profile.

CONCLUSIONS: Over 3 years, donanemab-treated participants with early symptomatic AD demonstrated increasing clinical benefits and a consistent safety profile, with limited-duration dosing.

TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT04437511.},
}

@article {pmid41330635,
year = {2025},
author = {Crowe, A and Yao, Y and Newman, M and Hoxha, K and Baffic, T and Brunden, KR},
title = {HDAC6 Inhibition Reduces Seeded Tau and α-Synuclein Pathologies in Primary Neuron Cultures and Wild-type Mice.},
journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1523/JNEUROSCI.1092-25.2025},
pmid = {41330635},
issn = {1529-2401},
abstract = {A previous compound screen identified two molecules with histone deacetylase 6 (HDAC6) inhibitory activity that reduced Alzheimer's disease (AD)-like tau inclusions in a primary rat cortical neuron model seeded with AD-brain derived tau fibrils. Testing here of additional HDAC6-selective inhibitors confirmed that compounds of this type decreased neuronal tau inclusions. Moreover, HDAC6 inhibitors also reduced Parkinson's disease (PD)-like α-synuclein aggregates in primary neurons seeded with recombinant α-synuclein fibrils. Knockdown of HDAC6 expression through treatment of seeded neuron cultures with AAV harboring HDAC6-specific shRNA also resulted in a reduction of tau and α-synuclein inclusions. Multiple compounds were evaluated for their ability to inhibit brain HDAC6 in mice, and ACY-738 was found to effectively inhibit brain HDAC6 activity upon oral dosing. ACY-738 was utilized in an efficacy study in which tau and α-synuclein pathologies were induced in wild-type mice through intracerebral injections of AD-brain derived tau and α-synuclein fibrils. Groups of male and female mice first received ACY-738 in drinking water one day prior to (pre-seeding) or one week after (post-seeding) brain injections of fibrils, followed by continued dosing for an additional 3 months. A control group of fibril-injected mice received water without ACY-738. Immunohistochemical evaluations revealed that ACY-738 administration resulted in significant reductions of tau pathology in both dosing schemes. Moreover, α-synuclein pathology was significantly reduced in mice with pre-seeding ACY-738 administration, with a strong trend toward reduction after post-seeding dosing. These results suggest that HDAC6 inhibitors have potential for the treatment of AD, PD and related diseases.Significance Statement The spread and abundance of brain tau pathology correlate with AD patient cognitive status, and there are presently no approved drugs that target tau. We demonstrate that HDAC6 inhibition or knockdown reduce both tau and α-synuclein inclusions that develop in wild-type rodent neuron models. A preferred HDAC6 inhibitor, ACY-738, was identified that inhibits brain HDAC6 when administered orally to mice. This compound was examined in a wild-type mouse model that develops concurrent seeded tau and α-synuclein brain inclusions. Significant reductions of both tau and α-synuclein inclusions were observed in mice dosed with ACY-738, suggesting that HDAC6 inhibition may be a therapeutic strategy for AD, PD and related diseases.},
}

@article {pmid41330156,
year = {2025},
author = {Costa, A and Provensi, G and Titi, C and Leri, M and Bucciantini, M and Ferraroni, M and Keeton, AB and Moore, AM and Piazza, GA and Abadi, AH and Angeli, A and Supuran, CT},
title = {Exploring dual inhibitors Carbonic Anhydrases and Phosphodiesterase 5 as potential agents for treatment Alzheimer's disease.},
journal = {European journal of medicinal chemistry},
volume = {303},
number = {},
pages = {118404},
doi = {10.1016/j.ejmech.2025.118404},
pmid = {41330156},
issn = {1768-3254},
abstract = {In this study, we report for the first time the design and evaluation of a series of compounds with potential therapeutic relevance for Alzheimer's disease (AD), able to inhibit both human Carbonic Anhydrase (hCA) isoforms most involved in this disease as well as Phosphodiesterase 5 (PDE5), using sildenafil as the structural scaffold. A total of 19 new dual-target molecules were synthesized and biologically assessed, leading to the identification of compound 8a as the most promising candidate, exhibiting potent inhibition toward both enzymatic targets. The binding interactions of three selected derivatives (6, 8a, and 10d) with hCA II were elucidated by X-ray crystallography experiments. Moreover, compound 8a demonstrated a favourable safety profile, as it did not markedly impair cell viability on differentiated SH-SY5Y at concentrations up to 100 μM and conferred protection against Aβ-induced cytotoxicity showing superior efficacy compared to the single-target reference agents acetazolamide (AAZ) and sildenafil in mitigating oxidative stress. In vivo, chronic administration of compound 8a prevented deficits in both recognition and working memory in Aβ1-42-infused mice, outperforming vehicle-treated controls. Collectively, these findings highlight the potential of dual CA/PDE5 inhibition as a novel therapeutic strategy for Alzheimer's disease.},
}

@article {pmid41316284,
year = {2025},
author = {Chen, C and Mo, M and Åkerman, M and Garcia-Ptacek, S and Xu, H and Eriksdotter, M},
title = {Dynamic associations of cholinesterase inhibitors and memantine with cognitive trajectories in individuals with Alzheimer's or mixed dementia: a real-world analysis using the quality registry SveDem.},
journal = {Alzheimer's research & therapy},
volume = {17},
number = {1},
pages = {256},
pmid = {41316284},
issn = {1758-9193},
abstract = {BACKGROUND: Alzheimer’s disease (AD) and mixed dementia (MxD) represent major public health concerns, yet there is limited real-world evidence on the long-term associations of commonly prescribed pharmacological treatments, particularly cholinesterase inhibitors (ChEIs) and their combination with memantine. This study aims to evaluate the long-term, time-varying associations of ChEIs and memantine on cognitive decline in a large, nationwide cohort of individuals diagnosed with AD or MxD.

METHODS: This observational study utilized data from the Swedish registry for cognitive/dementia disorders (SveDem), analyzing 32,282 individuals diagnosed with AD or MxD between 2007 and 2022. Patients were followed for up to 11 years to track treatment patterns and cognitive trajectories. Initiation of ChEIs (donepezil, galantamine, or rivastigmine) or memantine within six months after an AD or MxD diagnosis and then the time-varying medications (ChEIs alone, memantine alone or memantine added on to ChEIs) within six months after each follow-up were analyzed. Linear mixed-effects model was used to assess cognitive decline measured by Mini-Mental State Examination (MMSE) score trajectories.

RESULTS: Of the 32,282 participants (mean age 78.4 years; 61% women), 78.4% initiated treatment with ChEIs alone, and 21.6% with memantine alone. Over time, prescription patterns shifted from monotherapy to combination therapy, with donepezil and galantamine more likely to achieve 1 Defined Daily Dosages (DDD) than rivastigmine users. Memantine alone users experienced a yearly cognitive decline of 1.79 MMSE points (95% CI: −1.85, −1.73). Compared with memantine users, patients on ChEIs alone declined 0.65 points less per year (95% CI: −0.59, −0.72), while those on combination therapy declined 0.19 points less per year (95% CI: −0.10, −0.28). Among ChEIs, donepezil users experienced an annual decline of 1.02 points (95% CI: −1.06, −0.98). In comparison, galantamine users declined an additional 0.05 points per year (95% CI: −0.11, 0.01), and rivastigmine users declined an additional 0.17 points per year (95% CI: −0.24, −0.11), relative to donepezil.

CONCLUSIONS: In this large cohort of patients with AD or MxD, ChEIs users alone, particularly donepezil and galantamine, showed slower cognitive decline compared to users of memantine or combination therapy users. While differences were modest, the results contribute to a better understanding of treatment trajectories in routine clinical practice.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13195-025-01918-0.},
}

@article {pmid41329964,
year = {2025},
author = {Chen, M and Tang, G and Zhang, Y and Qian, ZJ},
title = {Exploring the Protective Effects of Two Alkaloids 1 and 2 from Aspergillus terreus C23-3 on Neuronal Cells by Combining Bioinformatics Prediction and Experimental Verification.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.5c00739},
pmid = {41329964},
issn = {1948-7193},
abstract = {Alzheimer's disease (AD) is an irreversible neurodegenerative disease that can lead to brain cell death and brain atrophy, manifested as memory loss, cognitive decline, and behavioral abnormalities. Its mechanism is complex, and there is currently no effective treatment method. The search for new therapies and natural drug candidates has become the focus of research. In recent years, marine-derived strains of Aspergillus terreus have become an important research direction for treating AD due to the unique structure and biological activity of their secondary metabolites. In this study, we investigated the potential of two alkaloids from Aspergillus terreus C23-3 in the treatment of AD through bioinformatics analysis and experimental validation. Bioinformatics analyses showed that the two alkaloids may act by modulating key targets associated with AD, especially alkaloid 2, which may exert significant therapeutic effects on AD by inhibiting glycogen synthase kinase-3β (GSK-3β) activity and reducing the level of hyperphosphorylation of Tau proteins. Molecular docking experiments showed that alkaloids 1 and 2 formed stable complexes with GSK-3β with a high affinity. Cellular experiments showed that alkaloids 1 and 2 could effectively inhibit apoptosis and injury in HT-22 cells. Further studies showed that alkaloid 2 reduced the phosphorylation level of Tau protein and attenuated oxidative-stress-induced neurological injury by inhibiting GSK-3β and its related pathways. These results suggest that alkaloid 2 has significant potential for AD therapy.},
}

@article {pmid41328628,
year = {2025},
author = {Ren, S and Singh, J and Gsteiger, S and Cogley, C and Reed, B and Abrams, KR and Dawoud, D and Owen, RK and Tappenden, P and Quinn, TJ and Bujkiewicz, S},
title = {Evaluating amyloid-beta as a surrogate endpoint in trials of anti-amyloid-beta drugs in Alzheimer's disease: a Bayesian meta-analysis.},
journal = {Journal of comparative effectiveness research},
volume = {},
number = {},
pages = {e250095},
doi = {10.57264/cer-2025-0095},
pmid = {41328628},
issn = {2042-6313},
abstract = {Aim: The use of amyloid-beta (Aβ) clearance to support regulatory approvals of drugs in Alzheimer's disease (AD) remains controversial. We evaluate Aβ as a potential trial-level surrogate endpoint for clinical function in AD. Materials & methods: Data on the effectiveness of anti-Aβ monoclonal antibodies (MABs) on Aβ and multiple clinical outcomes were identified from randomized controlled trials through a literature review. A Bayesian bivariate meta-analysis was used to evaluate Aβ as a surrogate endpoint for clinical function across all MABs and for each individual anti-Aβ MAB. The analysis for individual therapies was conducted in subgroups of treatments and by applying Bayesian hierarchical models to borrow information across treatments. Results: We identified 23 randomized controlled trials with 39 treatment contrasts for seven MABs. The surrogate relationship between treatment effects on Aβ and Clinical Dementia Rating-Sum of Boxes (CDR-SOB) across all MABs was strong: with a meaningful slope of 1.41 (0.60, 2.21) and small variance of 0.02 (0.00, 0.05). For individual treatments, the surrogate relationships were suboptimal, displaying large uncertainty. Sharing information across treatments considerably reduced the uncertainty, resulting in moderate surrogate relationships for aducanumab and lecanemab. No meaningful association was detected for other clinical outcomes, including Mini Mental State Examination and Alzheimer's Disease Assessment Scale-Cognitive Subscale. Conclusion: Although our results from the analysis of data across all MABs suggested that Aβ was a potential surrogate endpoint for CDR-SOB, individually the surrogacy patterns varied across treatments and showed no evidence of association. Bayesian information-sharing revealed moderate surrogate relationship only for aducanumab and lecanemab.},
}

@article {pmid41328259,
year = {2025},
author = {Shan, G and Cummings, J},
title = {Assessing safety and efficacy in subpopulations in Alzheimer's disease clinical trials: contextualizing representativeness.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {11},
number = {4},
pages = {e70186},
pmid = {41328259},
issn = {2352-8737},
abstract = {UNLABELLED: Efficacy outcomes in clinical trials are based on well-powered analyes of the entire participating population. Trial populations will comprise many types of demographic and biological subgroups, including individuals of different sexes, groups of older and younger individuals, participants with or without the apolipoprotein E ε4 (APOE) genotype, ethnoracial groups, participants from urban versus rural communities, participants with lower and higher educational levels, or individuals who have or have not undergone previous therapies such as anti-amyloid monoclonal antibodies (MABs). Each subgroups is underpowered to draw definitive outcomes, and analyses can lead to inaccurate conclusions. Disciplined subgroup analysis can be hypothesis generating and can help guide drug development decision-making. The risks associated with subgroup analysis can be mitigated by using standard terminology, prespecifying outcomes of interest, stratifying randomization, conducting interaction analyses to identify confounds, and limiting the number of subgroup comparisons. Alternative efficacy and safety analyses such as the interaction test and non-inferiority analyses may yield important insights. Together, these design and analytic straegies may allow trialists to avoid spurious interpretations and derive more informative conclusions regarding the impact of therapy on subgroups in Alzheimer's disease (AD) clinical trials. Greater understanding of safety and efficacy in the subgroups participating in trials is crtically important for indicating what conclusions can be generalized if the candidate therapy is approved.

HIGHLIGHTS: Clinical trials are sized to allow well-powered conclusions based on analysis of the entire participating population.Trial populations geared to be representative of the subgroups of the older population with AD are underpowered to allow drawing confident conclusions about efficacy or safety in subgroups.Strategies such as non-inferiority analysis combined with transparent reporting of the analytic framework may facilitate understanding treatment efficacy and safety in subgroups.},
}

@article {pmid41327837,
year = {2025},
author = {Padture, A and Gupta, S and Sivaram, A and Swamy, KV},
title = {Repurposing of Potential Curcumin Derivatives Against Cyclooxygenase-2 Using In Silico Methods and Its Implications in Neurological Disorders.},
journal = {Biotechnology and applied biochemistry},
volume = {},
number = {},
pages = {},
doi = {10.1002/bab.70106},
pmid = {41327837},
issn = {1470-8744},
abstract = {Cyclooxygenase-2 (COX-2) plays a crucial role in inflammatory responses and has been implicated in neuroinflammatory processes associated with neurological disorders such as Alzheimer's disease. While selective COX-2 inhibitors (coxib class of drugs) have been developed, their use is limited by adverse effects, necessitating the exploration of alternative therapeutic approaches. This study investigates the potential of curcumin derivatives as COX-2 inhibitors and their possible therapeutic applications in neurological disorders. Previous in silico studies show various amino acids interacting with naturally occurring curcumin derivatives. We explored the potential of 2561 curcumin derivatives as COX-2 enzyme inhibitors by examining their binding affinity to the protein. Using molecular docking, we assessed their interactions with two regions of COX-2, identifying five standout compounds with powerful binding affinities. The binding energies of these compounds lie around -10.7 and -10.6 kcal/mol. To better understand how these top candidates behave in a dynamic biological environment, we ran molecular dynamics simulations focusing on their interactions with one part of the enzyme. These simulations revealed that the compounds formed stable complexes with COX-2, maintaining consistent hydrogen bonds and hydrophobic contacts throughout. RMSD and RMSF graphs exhibit greater stability of these compounds as compared to the control molecule. Finally, energy calculations confirmed that these interactions were not only stable but also energetically favorable, suggesting that several curcumin derivatives could be promising COX-2 inhibitors. This study provides valuable insights into the potential of curcumin derivatives as COX-2 inhibitors and their possible therapeutic applications in neurological disorders. The identified compounds warrant further investigation through in vitro and in vivo studies to validate their efficacy and safety as potential alternatives to current selective COX-2 inhibitors in the treatment of neuroinflammatory conditions.},
}

@article {pmid41327376,
year = {2025},
author = {Liu, LR and Li, L and Lu, LL and Fan, SJ and Liu, LZ and He, RB and Li, H and Xian, XH and Li, WB},
title = {Ceftriaxone alleviates mitochondrial damage through the inhibition of extrasynaptic NMDA receptor-mediated changes in intracellular calcium levels to improve cognitive deficits in APP/PS1 mice.},
journal = {Alzheimer's research & therapy},
volume = {17},
number = {1},
pages = {253},
pmid = {41327376},
issn = {1758-9193},
support = {H2024206387//Natural Science Foundation of Hebei Province/ ; 81971007//National Natural Science Foundation of China/ ; },
mesh = {Animals ; *Ceftriaxone/pharmacology/therapeutic use ; *Mitochondria/drug effects/metabolism ; Mice ; *Calcium/metabolism ; *Receptors, N-Methyl-D-Aspartate/metabolism/antagonists & inhibitors ; *Cognitive Dysfunction/drug therapy/metabolism ; Mice, Transgenic ; Mice, Inbred C57BL ; Presenilin-1/genetics ; Male ; Amyloid beta-Protein Precursor/genetics ; Disease Models, Animal ; Alzheimer Disease/metabolism ; Hippocampus/drug effects/metabolism ; Excitatory Amino Acid Transporter 2/metabolism/genetics ; },
abstract = {BACKGROUND: Mitochondrial dysfunction and dysregulated calcium homeostasis contribute to Alzheimer's disease (AD) pathogenesis. The extrasynaptic N-methyl-D-aspartic acid (NMDA) receptor (eNMDAR) plays a crucial role in calcium influx and subsequent signaling cascades. In individuals with AD, the reduced expression and function of glutamate transporter-1 (GLT-1) result in glutamate spillover from the synaptic clefts to the extrasynaptic region, thereby activating eNMDAR and inducing mitochondrial damage. Ceftriaxone (Cef) has been reported to ameliorate cognitive deficits in APPswe/PS1dE9 (APP/PS1) mice by upregulating GLT-1. This study aimed to explore whether Cef alleviates mitochondrial dysfunction to improve cognitive impairment and the roles of GLT-1 and eNMDAR, particularly the participation of eNMDAR-induced intracellular calcium signaling in this process.

METHODS: C57BL/6J, APP/PS1, and GLT-1-knockdown APP/PS1 mice were used. NMDA (1 mM, 2 µL per ventricle) was injected cerebroventricularly into APP/PS1 mice once to activate eNMDAR. Cef (200 mg/kg) was intraperitoneally administered for 14 days. Cognitive function was evaluated by novel object recognition, novel location recognition and Morris water maze tests. Hippocampal mitochondrial ultrastructure was observed using transmission electron microscopy. Hippocampal mitochondrial membrane potential (MMP) was detected using JC-1 staining. The expression of eNMDAR and proteins related to mitochondrial biogenesis and dynamics was evaluated by western blot. A neuron‒astrocyte coculture derived from the cerebral cortex of embryonic mice was used to evaluate the effects of Cef on eNMDAR-induced neuronal calcium influx, mitochondrial calcium accumulation and MMP loss using live-cell imaging.

RESULTS: Cef treatment attenuated hippocampal mitochondrial dysfunction, including ultrastructural damage, reduced aspect ratio, dysregulation of MMP, impaired biogenesis and dynamics, and cognitive deficits, and prevented the upregulation of eNMDAR expression in APP/PS1 mice in a GLT-1-dependent manner. These protective effects on hippocampal mitochondrial dysfunction and cognitive deficits were counteracted by eNMDAR activation. Furthermore, Cef incubation inhibited eNMDAR-mediated calcium influx in a GLT-1-dependent way and reduced MMP in primary cortical neurons. Notably, Cef incubation significantly suppressed mitochondrial calcium overload, which was mechanistically linked to the observed decline in MMP.

CONCLUSIONS: Cef treatment prevented the upregulation of eNMDAR expression and the subsequent extracellular calcium influx in a GLT-1-dependent manner, thereby reducing mitochondrial calcium loading and ultimately mitigating mitochondrial damage and cognitive deficits in APP/PS1 mice.},
}

Animals
*Ceftriaxone/pharmacology/therapeutic use
*Mitochondria/drug effects/metabolism
Mice
*Calcium/metabolism
*Receptors, N-Methyl-D-Aspartate/metabolism/antagonists & inhibitors
*Cognitive Dysfunction/drug therapy/metabolism
Mice, Transgenic
Mice, Inbred C57BL
Presenilin-1/genetics
Male
Amyloid beta-Protein Precursor/genetics
Disease Models, Animal
Alzheimer Disease/metabolism
Hippocampus/drug effects/metabolism
Excitatory Amino Acid Transporter 2/metabolism/genetics

@article {pmid41327179,
year = {2025},
author = {Eshak, D and Arumugam, M},
title = {Nanomaterials: an overview of current trends and future prospects in neurological disorder treatment.},
journal = {Journal of translational medicine},
volume = {23},
number = {1},
pages = {1366},
pmid = {41327179},
issn = {1479-5876},
mesh = {Humans ; *Nervous System Diseases/therapy/drug therapy ; *Nanostructures/therapeutic use/chemistry ; Animals ; Blood-Brain Barrier ; },
abstract = {The World Health Organization (WHO) has identified neurological disorders (NDs) as one of the major health concerns worldwide, resulting in high mortality rates. NDs are conditions affecting the central and peripheral nervous systems, including the brain, spinal cord, cranial nerves, peripheral nerves, nerve roots, neuromuscular junctions, and muscles. These neurological diseases include Alzheimer's disease, Parkinson's disease, glioma/brain cancer, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, neuroinfections, ischemic stroke, trauma, hypoxia/anoxia, and depression. Unfortunately, these disorders remain difficult to treat due to the limited ability of conventional drugs to cross the blood-brain barrier (BBB) and achieve significant pharmacological effects in the brain. There is an urgent need to develop methods that can enhance drug efficacy and bypass the BBB. The application of various nanomaterials represents a promising approach to address these neurological disorders. Drugs incorporated with nanomaterials help improve therapeutic outcomes, reduce toxicity, provide better stability, enable targeted delivery, and enhance drug loading capacity. Numerous types and morphologies of inorganic and organic nanomaterials are increasingly employed for treating NDs, including quantum dots, dendrimers, metal nanoparticles, polymeric nanoparticles, liposomes, carbon nanotubes, metal oxide nanoparticles, and micelles. Their exceptional properties such as sensitivity, selectivity, and potential to bypass the BBB make them suitable for both diagnosis and treatment of NDs. In this review article, we briefly summarize the etiology and pathophysiology of various NDs along with current literature highlighting the use of nanomaterials for treating neurological disorders.},
}

Humans
*Nervous System Diseases/therapy/drug therapy
*Nanostructures/therapeutic use/chemistry
Animals
Blood-Brain Barrier

@article {pmid41326296,
year = {2025},
author = {Welchman, AE and Kourtzi, Z},
title = {Solving the 'Goldilocks problem' in dementia clinical trials with multimodal AI.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {},
number = {},
pages = {100397},
doi = {10.1016/j.tjpad.2025.100397},
pmid = {41326296},
issn = {2426-0266},
abstract = {The development of effective therapeutics for Alzheimer's Disease and related dementias (ADRD) has been hindered by patient heterogeneity and the limitations of current diagnostic tools. New treatments have no chance of working if given to patients who cannot benefit from them. This perspective explores how advances in Artificial Intelligence (AI), particularly multimodal machine learning, can solve the 'Goldilocks problem' of identifying patients for inclusion in clinical trials and support precision treatment in real-world healthcare settings. We examine the challenges of patient stratification, grounded by a conceptual framework of identifying each person's stage and subtype of dementia. We review data from several clinical trials of Alzheimer's disease therapeutics, to explore how AI-guided patient stratification can improve trial outcomes, reduce costs and improve recruitment. Further, we discuss the integration of AI into clinical workflows, the importance of model interpretability and generalizability, and ethical imperative to address algorithmic bias. By combining AI with scientific insight, clinical expertise, and patient experience, we argue that intelligent analytics can accelerate the discovery and delivery of new diagnostics and therapeutics, ultimately transforming dementia care and improving outcomes for patients around the globe.},
}

@article {pmid41326295,
year = {2025},
author = {Au, R and Popp, Z and Low, S and Ashton, NJ and Zetterberg, H},
title = {Reinventing "N" in the A/T/N framework: The case for digital.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {},
number = {},
pages = {100395},
doi = {10.1016/j.tjpad.2025.100395},
pmid = {41326295},
issn = {2426-0266},
abstract = {Breakthroughs in biomarkers for amyloid (A), tau (T), and neurodegeneration (N) have advanced the prospects of accurate Alzheimer's disease (AD) diagnosis. However, presence of pathology does not always translate into clinical expression and there are still clear knowledge gaps as to whether someone with AD biological indicators will lead to clinically apparent disease necessary to warrant drug treatments that carry toxicity risk. Reliance on decades-old assessment tools inhibits detection and monitoring at preclinical and early disease stages when new treatments could prove most effective. Evidence has accumulated that digital measures provide accurate detection of disease at early stages. We call for a re-evaluation of the A/T/N diagnostic framework, with digital evaluation measures complementing non-AD specific neurodegeneration markers, and even potentially replacing those non-specific to AD, to provide a clinically relevant feature critical to clinical trial advances and treatment decisions. Achieving this will only be possible if further research into novel digital evaluation tools is pursued with the same support and consideration as amyloid and tau.},
}

@article {pmid41325816,
year = {2025},
author = {Farhana, F and Sultana, MA and Hia, RA and Hegde, V},
title = {Postmenopausal Sarcopenia and Alzheimer's disease: The interplay of Mitochondria, Insulin resistance, and Myokines.},
journal = {Neuroscience and biobehavioral reviews},
volume = {},
number = {},
pages = {106501},
doi = {10.1016/j.neubiorev.2025.106501},
pmid = {41325816},
issn = {1873-7528},
abstract = {As life expectancy increases, cognitive impairments such as Alzheimer's disease (AD) create serious problems for older adults. Women regardless of ethnicity and age group, are disproportionately affected, accounting for two-thirds of AD cases, with post-menopausal women representing over 60% of those affected. Sarcopenia, defined by gradual reduction of skeletal muscle mass, strength, and activities, is increasingly correlated with an elevated risk of cognitive decline in post-menopausal women. Menopause-related hormonal decline (particularly estrogen loss) and aging contribute to sarcopenia, characterized by muscle mitochondrial dysfunction, oxidative stress, and insulin resistance. This sarcopenia-driven reduction in muscle mass and functional capacity further reduces the production of myokines (e.g., BDNF, irisin), impairing neuronal proliferation, adult neurogenesis, and spatial learning/memory. These pathophysiological changes show a contributing link between sarcopenia and AD progression in post-menopausal women. This review is unique in that it discusses the triangular interplay between menopause, sarcopenia, and AD, offering an integrated mechanistic framework that links hormonal decline, muscle loss, and neurodegeneration. We aim to clarify the pathophysiological causes behind the muscle-brain axis and suggest viable treatment approaches to slow down sarcopenia and cognitive deterioration in postmenopausal women based on current evidence. The formulation of targeted strategies for enhancing the quality of life and lessening healthcare expenditures in this expanding population depends on the advancement of understanding this complex interconnection between menopause, sarcopenia and cognition.},
}

@article {pmid41325201,
year = {2025},
author = {Zhao, N and Wang, Y and Yang, S and Guo, W and Li, Z and Cao, H and Zhang, Z and Li, Y and Chen, D and Xia, S and Xie, Z and Qu, Y and Wu, Y and Li, J and Yi, L and Wang, G and Guo, M},
title = {Surgical Protocols for Deep Cervical Lymphovenous Anastomosis in a Rat Model: Lymph Node and Lymphatic Vessel Anastomoses.},
journal = {Journal of visualized experiments : JoVE},
volume = {},
number = {225},
pages = {},
doi = {10.3791/69201},
pmid = {41325201},
issn = {1940-087X},
mesh = {Animals ; *Lymphatic Vessels/surgery ; *Anastomosis, Surgical/methods ; Rats ; *Lymph Nodes/surgery ; Neck/surgery ; *Veins/surgery ; Female ; },
abstract = {Deep cervical lymphovenous anastomosis (dcLVA) has become a promising treatment strategy for Alzheimer's disease (AD), offering significant improvements compared to the current limited treatment options. However, the underlying mechanism of dcLVA remains unclear. Although clinical trials are ongoing, animal models simulating dcLVA provide a valuable tool for exploring its mechanism. This study aims to develop a standardized protocol for creating dcLVA models in animals to facilitate basic research and address clinical challenges. We describe the surgical procedures and key steps for anastomosing the deep cervical lymph node (dcLN) and its afferent lymphatic vessel (ALV) with the posterior facial vein (PFV), detailing these two distinct surgical methods: deep cervical lymph node-vein anastomosis (dcLnVA) and deep cervical lymphatic vessel-vein anastomosis (dcLaVA). Beyond promoting lymphatic drainage, the comparison of these two surgical methods also helps us to understand and explore the role of the deep cervical lymph node and deep cervical lymphatic system in the pathogenesis of AD. Overall, the complete and clear presentation of the surgical procedure and key anatomical landmarks in the rat helps to standardize the surgical protocol, which can minimize confounding factors and reduce inter-experimental variability, thus laying a solid methodological foundation for a deeper understanding of the mechanisms involved.},
}

Animals
*Lymphatic Vessels/surgery
*Anastomosis, Surgical/methods
Rats
*Lymph Nodes/surgery
Neck/surgery
*Veins/surgery
Female

@article {pmid41324859,
year = {2025},
author = {Shi, C and Dong, J and Hui, X and Xu, Z and Zhao, Z and Dong, L},
title = {Production, Mechanisms, and Therapeutic Strategies of Tryptophan Metabolites in CNS Diseases.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {226},
pmid = {41324859},
issn = {1559-1182},
support = {22XYJ0002//Xi'an Innovation Capability Strong Foundation Plan/ ; },
mesh = {Humans ; *Tryptophan/metabolism ; Animals ; *Central Nervous System Diseases/metabolism/therapy/drug therapy ; Gastrointestinal Microbiome/physiology ; },
abstract = {Tryptophan (TRP) metabolites, which are produced from TRP via three pathways-kynurenine, 5-hydroxytryptamine, and indole-are key signaling molecules of the gut-brain axis and are involved in a variety of central nervous system (CNS) disease processes, such as Alzheimer's disease, depression, and schizophrenia by orchestrating inflammatory responses, redox imbalances, neurotransmitter dynamics, mitochondrial dysfunction, and apoptotic/autophagic pathways. However, TRP metabolites exhibit bidirectional modulatory effects, combining different neuroprotective and neurotoxic substances, depending on their metabolic environment and concentration thresholds, posing significant challenges for therapeutic strategies. Therefore, it is important to modulate TRP metabolite production factors, including the regulation of key enzymes in metabolic pathways, the gut microbiota, hormones, and the disease pathology microenvironment, to promote the production of neuroprotective metabolites and inhibit neurotoxic metabolite production. In this review, we detail the influencing factors affecting TRP metabolite production, the regulatory role of TRP metabolites in CNS disorders, and therapeutic strategies related to TRP metabolites for CNS disorders. Targeting TRP metabolizing enzymes or remodeling the ecology of the gut microbiota could be a new strategy for the treatment of CNS diseases, providing a theoretical basis for future precision intervention in CNS diseases.},
}

Humans
*Tryptophan/metabolism
Animals
*Central Nervous System Diseases/metabolism/therapy/drug therapy
Gastrointestinal Microbiome/physiology

@article {pmid41323809,
year = {2025},
author = {Horgan, NG and Djurovic-Topalovic, A and Ademoye, TA and Reyes-Charles, HI and Kobayashi, N and Plascencia-Villa, G and Perry, G and Murakami, T and Fortin, JS},
title = {Epigallocatechin-3-Gallate: A potential amyloid Fibril Disaggregator of Serum amyloid A1.},
journal = {Biochemistry and biophysics reports},
volume = {44},
number = {},
pages = {102365},
pmid = {41323809},
issn = {2405-5808},
abstract = {Serum amyloid A1 (SAA1) is a 122-amino acid protein that, after cleavage, matures into a 104-amino acid form. Its N-terminus is responsible for binding high-density lipoprotein (HDL), while the C-terminus maintains its structural integrity. As an acute-phase protein, SAA1 is produced by the liver in response to acute inflammation. SAA1 is also a precursor to amyloid A (AA), and its accumulation can lead to AA amyloidosis-a condition secondary to chronic inflammation that causes tissue damage and organ dysfunction. Our study explores methods to disaggregate SAA1 fibrils isolated from the cat spleen, chicken liver, and cow liver. Specifically, we investigate the use of epigallocatechin-3-gallate (EGCG), a polyphenolic flavonoid extracted from green tea known for its anti-inflammatory and antioxidant properties, to disaggregate these fibrils. Dynamic light scattering (DLS) and transmission electron microscopy (TEM) were used to analyze these fibrils after treatment with 1 % DMSO and 400 μM of EGCG in 10 mM PBS (pH 7.4). The results demonstrated that EGCG effectively reduced fibril size, as confirmed by DLS characterization, with the disappearance or diminished prominence of the 10[3-4] nm peak. Additional TEM results confirmed that EGCG disaggregated amyloid-beta fibrils isolated from Alzheimer's disease brains. These findings suggest that compounds like EGCG could be valuable in treating inflammatory and neurodegenerative conditions by disaggregating amyloid fibrils.},
}

@article {pmid41323723,
year = {2025},
author = {Dewangan, B and Swain, P and Patra, S and Bodhe, PR and Kulkarni, N and Sahu, B},
title = {Synthesis and evaluation of HFIP bearing triazolo-amides as amyloid-β aggregation inhibitors and suppressors of aggregation induced neuroinflammation.},
journal = {RSC medicinal chemistry},
volume = {},
number = {},
pages = {},
pmid = {41323723},
issn = {2632-8682},
abstract = {Alzheimer's disease (AD) is a complex neurodegenerative disease with biological signatures of amyloid beta (Aβ) aggregated plaques and increased levels of bio-metals like copper (Cu), zinc (Zn), and iron (Fe). Aβ-induced lysosomal membrane permeabilization is a key event in neuronal injury in AD. Aβ aggregation also modulates mitochondria membrane potential (MMP), activates interleukin 1β and NLRP3 inflammasome eventually leading to increased reactive oxygen species (ROS) production, neuronal apoptosis and mitochondrial dysfunction. Here, we report a multi-functional compound (2f) identified through structure-activity relationship study from a series of polyfluorinated triazole compounds. Compound 2f suppressed metal induced aggregation, downregulated NLRP3 inflammasome and IL-1β expression. It has maintained the lysosomal acidic pH and restored mitochondrial membrane potential. HFIP bearing triazolo amide (2f) was found to chelate with Cu(ii) and Zn(ii) selectively in the presence of a range of other physiologically relevant metals. Further, a molecular dynamics (MD) simulation study revealed 2f disrupted the aggregation via interacting with chain A of pentameric Aβ. Therefore the HFIP bearing triazole amides may serve as potential scaffolds for drug development towards the treatment of AD.},
}

@article {pmid41322563,
year = {2025},
author = {Dias, AJ and Sena Oliveira, A and Silva, AC and Braga, AL},
title = {Rational Design and Greener Synthesis of Selenylated Indolamides as Potential Anti-Alzheimer's Agents.},
journal = {ACS omega},
volume = {10},
number = {46},
pages = {56334-56348},
pmid = {41322563},
issn = {2470-1343},
abstract = {This study presents the rational design and sustainable synthesis of selenylated indolamides as potential therapeutic agents for Alzheimer's disease. Through computational approaches, including molecular docking and pharmacokinetic analyses, we identified key structural modifications that improve acetylcholinesterase inhibition, a critical target for AD treatment. We employed an environmentally benign I2/DMSO oxidation system to optimize the synthetic protocol, enabling the efficient selenylation of 27 indolamide derivatives (5a-6a) via a straightforward and practical transformation, delivering high yields of up to 99%. Importantly, the methodology proved scalable, delivering an 88% yield on a gram-scale reaction. In silico ADMET predictions using the pkCSM platform indicated that C2-selenylated indolamides possess an improved safety profile and promising pharmacokinetic properties, suggesting their potential for further drug development. In particular, compounds 5a and 5y demonstrated the best balance between reaction yield and docking score (94% and 86.17; 98% and 93.71, respectively). These findings highlight the significance of incorporating green chemistry principles alongside advanced in silico methodologies to drive innovation in drug discovery.},
}

@article {pmid41322352,
year = {2025},
author = {Liu, S and Zhao, M and Liu, Y and Yang, X and Yan, H and Xu, H and Wu, Y and Xu, Y},
title = {Comparative efficacy and safety of symptomatic therapy and disease-modifying therapy for Alzheimer's disease: a systematic review and network meta-analysis.},
journal = {Frontiers in neuroscience},
volume = {19},
number = {},
pages = {1656906},
pmid = {41322352},
issn = {1662-4548},
abstract = {BACKGROUND: The management of Alzheimer's disease has shifted toward disease-modifying therapies aimed at delaying disease progression rather than focusing solely on symptomatic treatment. This study summarizes the latest evidence regarding the benefits and harms of anti-Alzheimer's disease drugs.

METHODS: We conducted a comprehensive review of randomized controlled trials from PubMed, Embase, Cochrane Library, Web of Science databases, and other sources up to April 2025. Two researchers independently reviewed the literature and analyzed the data. A network meta-analysis was performed using Review Manager version 5.3 and Stata version 18.0 to calculate mean differences (MDs) and 95% confidence intervals (CIs) for direct and indirect comparisons. Treatment efficacy was evaluated using the Surface Under the Cumulative Ranking Curve (SUCRA). Bias was assessed using the Revised Cochrane Risk of Bias Tool version 2.0, and publication bias was analyzed with funnel plots.

RESULTS: The network meta-analysis included 23 randomized controlled trials with 16,010 participants, evaluating nine pharmacological interventions ranging from traditional symptomatic therapies to four United States Food and Drug Administration- and National Medical Products Administration-approved disease-modifying therapies, notably anti-amyloid beta monoclonal antibodies. Aducanumab significantly improved ADAS-cog scores compared with placebo (MD -5.97, 95%CI -10.33, -1.61; SUCRA: 93.0%) and demonstrated notable improvements in ADCS-ADL scores (MD 4.99, 95%CI 2.27, 7.72; SUCRA: 98.6%). Memantine ranked highest for neuropsychiatric symptoms (SUCRA: 80.8%). Aducanumab also had the highest SUCRA for CDR-SB (91.5%) and showed moderate superiority in MMSE scores (MD 3.55, 95%CI 1.35, 5.75; SUCRA: 98.2%).

CONCLUSION: Symptomatic treatments, especially memantine for neuropsychiatric symptoms, remain effective. However, the network meta-analysis indicates that, for patients with mild cognitive impairment or mild Alzheimer's disease, aducanumab demonstrates the greatest potential for cognitive and clinical improvement (MMSE, ADAS-cog, ADCS-ADL), despite associated risks such as adverse events and amyloid-related imaging abnormalities linked to disease-modifying therapies. Lecanemab provides moderate benefits, while donanemab appears less effective. Thus, clinicians should apply disease-modifying therapies cautiously and individually, carefully balancing potential risks and benefits for each patient.

PROSPERO [CRD42025637730], https://www.crd.york.ac.uk/PROSPERO/.},
}

@article {pmid41322300,
year = {2025},
author = {Domínguez-Fernández, C and Kumar, A and Kumar, R and Darreh-Shori, T},
title = {From heart to brain: cognitive potential of propranolol and diltiazem through cholinergic enhancement via butyrylcholinesterase inhibition.},
journal = {Frontiers in pharmacology},
volume = {16},
number = {},
pages = {1694610},
pmid = {41322300},
issn = {1663-9812},
abstract = {BACKGROUND: Butyrylcholinesterase (BChE) has emerged as a promising therapeutic target in the treatment of Alzheimer's disease (AD), particularly in its later stages when acetylcholinesterase (AChE) activity declines. Drug repurposing offers a strategic approach to identify novel BChE inhibitors among existing FDA-approved compounds.

OBJECTIVE: This study aimed to evaluate the cholinesterase inhibitory potential of propranolol and diltiazem-two widely used cardiovascular drugs-through in silico modelling and in vitro and ex vivo enzyme-inhibition kinetic.

METHODS: Molecular docking was performed using AutoDock Vina to assess the binding affinity of propranolol and diltiazem to AChE and BChE. In vitro screening and inhibition were measured using a modified Ellman's assay with human recombinant AChE and plasma-derived BChE. Ex-vivo IC50 and Ki values were determined through kinetic analyses in pooled plasma samples, and inhibition modes were characterized using nonlinear regression models.

RESULTS: Both propranolol and diltiazem selectively inhibited BChE, with minimal activity against AChE. At 100 μM, BChE inhibition exceeded 80% for both compounds, while AChE inhibition was limited to 18% (propranolol) and 2% (diltiazem). Propranolol exhibited a Ki of 0.19 µM, comparable to the selective BChE inhibitor ethopropazine (Ki = 0.15 µM), and acted as a competitive inhibitor. Diltiazem exhibited a higher Ki of 2.3 µM. These effects were observed at concentrations within or near reported brain levels for propranolol, suggesting potential in vivo relevance.

CONCLUSION: Propranolol and diltiazem demonstrate selective BChE inhibition, with propranolol showing potency comparable to established potent BChE inhibitors. Given their established safety profiles and CNS activity, these compounds represent promising candidates for repurposing in the treatment of AD and other cognitive disorders. Further in vivo studies are warranted to explore their therapeutic potential.},
}

@article {pmid41321177,
year = {2025},
author = {Sahakian, BJ},
title = {The role of psychopharmacology and cognitive neuroscience in understanding the brain in the treatment of psychiatric disorders and neurological diseases for the benefit of society.},
journal = {Journal of psychopharmacology (Oxford, England)},
volume = {},
number = {},
pages = {2698811251397329},
doi = {10.1177/02698811251397329},
pmid = {41321177},
issn = {1461-7285},
abstract = {This perspectives piece reflects on some of the major scientific contributions in psychopharmacology, cognitive neuroscience, and public policy of Professor Barbara J. Sahakian, Commander of the Most Excellent Order of the British Empire (CBE). Her pioneering research has advanced the understanding of brain mechanisms, including neurotransmitter modulation, and psychological processes involved in cognition, emotion, and motivation, leading to novel treatments for disorders such as Alzheimer's disease, attention deficit hyperactivity disorder, obsessive-compulsive disorder, and depression. She has also contributed to a better understanding of brain mechanisms underlying and psychological processes involved in these disorders. She has championed early detection of Alzheimer's disease through neuropsychological tools, such as the Cambridge Neuropsychological Test Automated Battery (CANTAB) paired associates learning (PAL) test and contributed to identifying cognitive and neural changes in Huntington's disease gene carriers. Beyond clinical research, Sahakian has influenced public health policy through initiatives such as the UK Government Foresight Project on Mental Capital and Wellbeing and the National Institute for Health and Care Excellence guidelines on gambling-related harms. She has also led efforts in neuroethics and public engagement, co-authoring accessible science books and participating in global forums. Recent research emphasises preventative psychiatry, including lifestyle interventions, such as diet, sleep, social connection, and lifelong learning as preventive strategies for cognitive decline and mental health problems. Through interdisciplinary collaborations and mentorship, Sahakian continues to inspire the next generation of scientists to pursue innovative research for societal benefit in neuropsychopharmacology and cognitive neuroscience.},
}

@article {pmid41320930,
year = {2025},
author = {Suthar, T and Maurya, R and Sonwani, A and Upadhayay, P and Datusalia, AK and Naqvi, S and Jain, K},
title = {Nose-to-Brain Delivery of Donepezil Hydrochloride via Oleic Acid-Conjugated PAMAM G4 Dendrimers for the Treatment of Alzheimer's-Like Dementia.},
journal = {Molecular pharmaceutics},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.molpharmaceut.5c00761},
pmid = {41320930},
issn = {1543-8392},
abstract = {Alzheimer's disease (AD) is a complex, progressive neurodegenerative disorder characterized by dementia and cognitive impairments. Acetylcholinesterase (AChE) inhibitors are generally prescribed for clinical management of AD symptoms. Donepezil hydrochloride (DPZ) is a reversible, selective, and noncompetitive inhibitor of AChE recommended for the treatment of mild-to-moderate AD. However, a higher dose of this drug must be administered to achieve adequate therapeutic concentrations in the brain, leading to peripheral side effects. In the present research work, oleic acid (OA) conjugated PAMAM G4 dendrimers (OA-G4) are explored for delivering DPZ to the brain. OA was conjugated to PAMAM G4 dendrimers using EDC conjugation chemistry, and the conjugation was confirmed by nuclear magnetic resonance (NMR) and Fourier-transform infrared (FTIR) spectroscopy. DPZ was successfully loaded on the OA-G4 conjugate, and the loading and entrapment efficiency were found to be 78.59% ± 5.52% and 62.12% ± 0.67%, respectively. The drug release studies showed a faster release of DPZ from the DPZ-OA-G4 conjugate for the initial 6 h, followed by a sustained release, with 68.44% ± 1.88% of the drug released in 24 h. Cytotoxicity studies in SH-SY5Y cells demonstrated the safety and cytocompatibility of the conjugate at a wide range of concentrations. Cell internalization study revealed deep localization of the dendrimeric nanoconjugate in SH-SY5Y cells. Biodistribution studies of the OA-G4 conjugate through the intranasal route, using an IVIS whole-body live imaging system, demonstrated abundant fluorescence in the brain, indicating efficient brain targeting via nose-to-brain delivery. Neurobehavior studies in male SD rats suggested significant attenuation of AlCl3-induced cognitive decline in DPZ-OA-G4 treated animals, which was further confirmed with biochemical and histological evaluations. In conclusion, this study provides proof of concept that DPZ can be successfully targeted to the brain using ligand-conjugated dendrimeric systems via intranasal administration, a noninvasive route that enables direct nose-to-brain delivery, bypasses the blood-brain barrier, and minimizes systemic side effects.},
}

@article {pmid41319675,
year = {2025},
author = {Langbaum, JB and Bradbury, AR and Egleston, BL and McCarty Wood, E and Langlois, CM and Largent, EA and Harkins, K and Erickson, CM and Stites, SD and Oyen, E and Riviere, ME and Liu, F and Graf, A and Kim, SYH and Grill, JD and Reiman, EM and Tariot, PN and Roberts, JS and Karlawish, J},
title = {Impact of learning APOE genotype on cognitively unimpaired adults: a pre-screening cohort study of the Alzheimer's Prevention Initiative Generation Study 1.},
journal = {The lancet. Healthy longevity},
volume = {},
number = {},
pages = {100778},
doi = {10.1016/j.lanhl.2025.100778},
pmid = {41319675},
issn = {2666-7568},
abstract = {BACKGROUND: The apolipoprotein E (APOE) gene is the best established genetic risk factor for Alzheimer's disease in later life, with the ε4 allele conferring higher risk. APOE disclosure is becoming increasingly common in the clinical care of people with Alzheimer's disease and in cognitively unimpaired adults. In this study, we aimed to describe changes in measures of genetic disease knowledge and psychiatric symptoms following APOE disclosure to cognitively unimpaired adults.

METHODS: Data were collected as part of the screening phase of the global, multicentre, Alzheimer's Prevention Initiative Generation Study 1 (NCT02565511). Eligible individuals were cognitively unimpaired (Mini-Mental State Exam total score ≥24), aged 60-75 years, and psychologically pre-screened for readiness (by measures of depressive symptoms and anxiety) to receive their APOE genotype from a health-care provider. Participants were assessed before disclosure, and 2-7 days, 6 weeks, 6 months, and 12 months after disclosure. Multivariable linear and ordinal logistic regressions were used to compare changes in genetic disease knowledge, anxiety, depression, and distress by APOE4 genotype status, adjusting for key covariates, with a focus on 2-7 days after disclosure. Multiple imputation by chained equations methods was used to account for missing outcome data.

FINDINGS: The trial took place between Nov 30, 2015, and Sept 23, 2019. In total, 9496 participants (including 790 APOE4 homozygotes, 4869 heterozygotes, and 3837 non-carriers) learned their APOE genotype from a health-care provider as part of Generation Study 1 screening. 4038 (42·5%) participants were in the 65-69-year age group, 5790 (61·0%) were female, 3706 (39·0%) were male, and 8862 (93·3%) self-identified as White. Increase in genetic disease knowledge 2-7 days after disclosure was greater in APOE4 homozygotes (mean 1·19 [SD 3·95]) than in heterozygotes (0·78 [3·95], p=0·042) and non-carriers (0·29 [3·96], p=0·0002). Disease-specific distress 2-7 days after disclosure increased more in homozygotes (2·25 [6·42]) than in heterozygotes (0·53 [5·08], p<0·0001) and non-carriers (0·79 [4·95], p<0·0001). Levels of anxiety 2-7 days after disclosure increased in homozygotes (0·17 [2·95]) but decreased in heterozygotes (-0·67 [2·68], p<0·0001) and non-carriers (-0·66 [2·67], p<0·0001). There were no significant changes in depressive symptoms following disclosure for any APOE4 group. Notably, for all APOE4 groups, increases in distress and anxiety were small and did not reach predefined levels of clinical concern.

INTERPRETATION: In cognitively unimpaired, psychologically pre-screened adults, APOE disclosure by a trained health-care provider was generally safe and well tolerated, consistent with results from previous studies. To our knowledge, this is the largest study experience of APOE disclosure to date, especially for homozygotes, and is notable for the older age of participants compared with previous research. These results are timely and important given anticipated increases in APOE disclosure to guide clinical decision making once an Alzheimer's disease prevention treatment is approved for cognitively unimpaired adults or if patients' family members are interested in genetic testing. Scalable approaches for returning Alzheimer's disease risk information are critical to meeting anticipated demand. Results from this study may be useful to bolster clinical translatability of disclosure programmes.

FUNDING: The National Institute on Aging, Alzheimer's Association, Banner Alzheimer's Foundation, GHR Foundation, F-Prime Biomedical Research Initiative (FBRI), and Novartis Pharma.},
}

@article {pmid41319153,
year = {2025},
author = {Wu, CY and Chen, L and Fatima, H and Gatchel, J and Das, S and Kivisäkk, P and Arnold, SE and Dodge, HH},
title = {Combined use of plasma p-tau217, NfL, and GFAP predicts domain-specific cognitive decline in cognitively unimpaired and MCI individuals.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {12},
pages = {e70934},
pmid = {41319153},
issn = {1552-5279},
support = {P30AG062421/GF/NIH HHS/United States ; R01AG051628/GF/NIH HHS/United States ; R01AG056102/GF/NIH HHS/United States ; K01AG088184/GF/NIH HHS/United States ; },
mesh = {Humans ; *tau Proteins/blood ; Male ; Female ; *Cognitive Dysfunction/blood/diagnosis ; *Glial Fibrillary Acidic Protein/blood ; *Neurofilament Proteins/blood ; Biomarkers/blood ; Aged ; Phosphorylation ; Neuropsychological Tests ; Aged, 80 and over ; },
abstract = {INTRODUCTION: Accurate identification of individuals at risk for cognitive decline is critical for treatment planning and trial enrichment strategies. We evaluated the combined utility of plasma phosphorylated tau at threonine 217 (p-tau217), neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP) in predicting domain-specific cognitive decline.

METHODS: Participants (n = 523; 40.9% cognitively unimpaired [CU]; 59.1% mild cognitive impairment [MCI]) were from the Massachusetts Alzheimer's Disease Research Center. Cognition was assessed using the National Alzheimer's Coordinating Center Uniform Data Set. Participants were classified as high(+)/low(-) for each biomarker using Gaussian mixture models.

RESULTS: Among all participants, high p-tau217 alone [p-tau217(+)NfL(-)GFAP(-)] was associated with a steeper decline in episodic/semantic memory and processing speed compared to the all-low group (p ≤ 0.02). With the addition of high GFAP [p-tau217(+)NfL(-)GFAP(+)], steeper decline extended to most cognitive domains, including global cognition and executive function, compared to the all-low group. In CU, faster decline in global cognition and executive function was seen when all biomarkers were elevated ([p-tau217(+)NfL(+)GFAP(+)]; p ≤ 0.04).

DISCUSSION: Combined plasma biomarkers predict decline in cognitive domains vulnerable to early disease.

HIGHLIGHTS: High phosphorylated tau at threonine 217 (p-tau217) alone was associated with declines in semantic/episodic memory, whereas its combination with elevated glial fibrillary acidic protein (GFAP) predicted declines in a wider range of cognitive domains. Elevated neurofilament light chain (NfL) amplifies the cognitive decline already driven by p-tau217 and GFAP. In cognitively unimpaired individuals, subtle domain-specific cognitive declines can be detected when both core and non-core Alzheimer's disease biomarkers are used. Our finding highlights the importance of focusing on vulnerable cognitive domains during early disease where global cognition may appear stable but specific impairments can be masked within composite scores.},
}

Humans
*tau Proteins/blood
Male
Female
*Cognitive Dysfunction/blood/diagnosis
*Glial Fibrillary Acidic Protein/blood
*Neurofilament Proteins/blood
Biomarkers/blood
Aged
Phosphorylation
Neuropsychological Tests
Aged, 80 and over

@article {pmid41318982,
year = {2025},
author = {Huang, Y and Guo, Y and Zhang, H and Deng, J and Huang, Z and Chen, A and Wu, X and Lin, D and Ye, P and Chen, X and Zheng, X},
title = {Repeated Exposure to Lidocaine Induces Alzheimer's-Like Cognitive Impairment Neuropathology in Aged Mice Through BDNF-Regulated Autophagy.},
journal = {Journal of cellular and molecular medicine},
volume = {29},
number = {23},
pages = {e70970},
pmid = {41318982},
issn = {1582-4934},
support = {82171186//National Natural Science Foundation of China/ ; 82471278//National Natural Science Foundation of China/ ; 2023Y9282//The Joint Funds for the Innovation of Science and Technology of Fujian Province/ ; 2023Y9315//The Joint Funds for the Innovation of Science and Technology of Fujian Province/ ; 2021QH1307//Startup Fund for scientific research, Fujian Medical University/ ; },
mesh = {Animals ; *Brain-Derived Neurotrophic Factor/metabolism ; *Autophagy/drug effects ; Mice ; *Lidocaine/adverse effects ; *Cognitive Dysfunction/pathology/metabolism/chemically induced ; *Alzheimer Disease/pathology/metabolism/chemically induced ; Hippocampus/pathology/metabolism/drug effects ; Male ; Signal Transduction/drug effects ; Receptor, trkB/metabolism ; Astrocytes/metabolism/drug effects/pathology ; Disease Models, Animal ; TOR Serine-Threonine Kinases/metabolism ; *Aging/pathology ; Amyloid beta-Peptides/metabolism ; Mice, Inbred C57BL ; },
abstract = {Lidocaine is widely used for perioperative pain management, but repeated exposure may cause neurotoxicity, including neurological deficits. This study investigates mechanisms underlying cognitive decline induced by repeated lidocaine exposure. Eighteen-month-old mice received repeated clinically relevant lidocaine infusions over 3 days. Cognitive function was assessed by Morris water maze, Y-maze and open field tests. Hippocampal pathology was examined via TEM, Nissl staining, immunofluorescence for astrocyte polarisation and Aβ deposition, and western blot for tau, BDNF, TrkB, mTOR and autophagy proteins. The TrkB agonist 7,8-DHF was used to modulate BDNF/TrkB/mTOR signalling. Repeated lidocaine exposure impaired cognition and induced Alzheimer's-like hippocampal pathology, as evidenced by increased accumulation of Aβ and tau toxic proteins, along with neuronal death. It reduced BDNF expression, inhibited TrkB phosphorylation, and activated mTOR signalling, leading to autophagy inhibition and pathological protein accumulation. Lidocaine shifted astrocytes towards the neurotoxic A1 phenotype, decreasing neuroprotective A2 astrocytes and BDNF synthesis. TrkB agonist treatment restored signalling, enhanced autophagy and improved cognitive deficits and pathology. Repeated lidocaine exposure promotes A1 astrocyte increase and A2 decrease, inhibiting autophagy via the BDNF/TrkB/mTOR pathway, resulting in toxic protein deposition and Alzheimer's-like cognitive impairment.},
}

Animals
*Brain-Derived Neurotrophic Factor/metabolism
*Autophagy/drug effects
Mice
*Lidocaine/adverse effects
*Cognitive Dysfunction/pathology/metabolism/chemically induced
*Alzheimer Disease/pathology/metabolism/chemically induced
Hippocampus/pathology/metabolism/drug effects
Male
Signal Transduction/drug effects
Receptor, trkB/metabolism
Astrocytes/metabolism/drug effects/pathology
Disease Models, Animal
TOR Serine-Threonine Kinases/metabolism
*Aging/pathology
Amyloid beta-Peptides/metabolism
Mice, Inbred C57BL

@article {pmid41318018,
year = {2025},
author = {de Souza, PC and Bezerra, TPW and de Melo Rêgo, MJB and da Rosa, MM},
title = {Advances in Neurological Therapies: A Review of Clinical Trials in Alzheimer's, Parkinson's, and Multiple Sclerosis.},
journal = {The American journal of medicine},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.amjmed.2025.11.025},
pmid = {41318018},
issn = {1555-7162},
abstract = {The period from 2020 to 2025 marked a pivotal juncture in the treatment of major neurological diseases, with Phase II-IV trials delivering the first compelling evidence for disease-modifying interventions in Alzheimer's disease, Parkinson's disease, and multiple sclerosis. This narrative review provides a critical analysis of this evolving therapeutic landscape, focusing on efficacy, safety, and practical implications. Our analysis reveals unprecedented yet heterogeneous progress. In Alzheimer's disease, anti-amyloid monoclonal antibodies (donanemab, lecanemab) achieved regulatory approval, establishing a new treatment paradigm despite modest efficacy and risks of amyloid-related imaging abnormalities (ARIA). In Parkinson's disease, GLP-1 receptor agonists (lixisenatide) demonstrated the first convincing disease modification signals in Phase II trials. For multiple sclerosis, the failure of Bruton's tyrosine kinase (BTK) inhibitors contrasted with the consolidation of anti-CD20 therapies as the therapeutic standard, refined by innovations in dosing and delivery. Collectively, these findings herald a new era of disease-modifying therapy in neurology, though current gains remain limited and dependent on biomarker stratification and safety monitoring. The challenge ahead is translating these successes into accessible, sustainable clinical benefits.},
}

@article {pmid41317176,
year = {2025},
author = {Pour, FT and Saadatpour, F and Salari, A},
title = {Comprehensive and In-Depth Molecular and Pathway Studies of the Hippocampus in Alzheimer's Disease.},
journal = {Cellular and molecular neurobiology},
volume = {45},
number = {1},
pages = {110},
pmid = {41317176},
issn = {1573-6830},
support = {CSBI14011102//Cognitive Science and Biology Institute (CSBI)/ ; SBNGC14011101//Systems Biology and Next Generation Company (SBNGC)/ ; },
mesh = {*Alzheimer Disease/genetics/metabolism/pathology ; Humans ; *Hippocampus/metabolism/pathology ; Protein Interaction Maps/genetics ; *Signal Transduction/genetics ; Gene Regulatory Networks ; Gene Expression Profiling ; Male ; Gene Expression Regulation ; Female ; },
abstract = {Alzheimer's disease (AD) still lacks a conclusive treatment, largely due to an incomplete understanding of the molecular mechanisms involved. To enhance our knowledge of AD pathogenesis and identify potential therapeutic targets, this study integrates differential gene expression analysis, pathway enrichment, hub gene discovery, protein-protein interaction (PPI) clustering, and transcription factor/protein kinase regulation into a single, cohesive pipeline. This comprehensive systems-level approach moves beyond single-gene analyses to offer a broader, mechanistically focused insight into AD biology. Using RNA-seq data from the CA1 region of the hippocampus-a subregion selectively affected in early AD-we identified 1,104 differentially expressed genes (DEGs). Among the enriched pathways, "7-alpha-hydroxycholesterol" was upregulated, while "vacuolar organization" was downregulated in AD samples. Furthermore, five novel hub genes (MRPS7, RPL5, GFM1, RAD51, and ASPM) were identified within the PPI network. The first three-MRPS7, RPL5, and GFM1-along with ACO2 and MT-ATP6, are potentially linked to hereditary forms of AD due to their roles in mitochondrial function. We also discovered four collaborative clusters within the network that notably associated with the "inflammatory response", "7-alpha-hydroxycholesterol", "Mitochondrial dysfunction" and "Oxidative phosphorylation" pathways, making them promising candidates for therapeutic and diagnostic investigation due their behavioral information members. Additionally, we identified ten transcription factors (GATA2, CHD1, THRA, IRF7, ZBTB48, POLE4, ZNF219, SLC2A4RG, NR1D1, and RXRA) and one protein kinase (PRKCZ) as potential regulatory elements in AD. This study broadens our understanding of Alzheimer's disease by identifying five candidate hub genes, two functional PPI clusters, two signaling pathways, and eleven regulatory proteins, thereby laying the groundwork for future therapeutic and diagnostic developments in molecular AD research.},
}

*Alzheimer Disease/genetics/metabolism/pathology
Humans
*Hippocampus/metabolism/pathology
Protein Interaction Maps/genetics
*Signal Transduction/genetics
Gene Regulatory Networks
Gene Expression Profiling
Male
Gene Expression Regulation
Female

@article {pmid41315790,
year = {2025},
author = {Dong, D and Ahmed, W and Sagar, R and Boyd, RJ and Mahairaki, V},
title = {Mapping key mitochondrial genes in Alzheimer's disease through human tissue and iPSC derived neurons.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {42766},
pmid = {41315790},
issn = {2045-2322},
support = {RF190106435;DFD-18159;T32AG0585279;//NIA;The Richman Family Precision Medicine Center of Excellence in Alzheimer's Disease at Johns Hopkins;National Institutes of Health/ ; RF190106435;DFD-18159;T32AG0585279;//NIA;The Richman Family Precision Medicine Center of Excellence in Alzheimer's Disease at Johns Hopkins;National Institutes of Health/ ; RF190106435;DFD-18159;T32AG0585279;//NIA;The Richman Family Precision Medicine Center of Excellence in Alzheimer's Disease at Johns Hopkins;National Institutes of Health/ ; RF190106435;DFD-18159;T32AG0585279;//NIA;The Richman Family Precision Medicine Center of Excellence in Alzheimer's Disease at Johns Hopkins;National Institutes of Health/ ; RF190106435;DFD-18159;T32AG0585279;//NIA;The Richman Family Precision Medicine Center of Excellence in Alzheimer's Disease at Johns Hopkins;National Institutes of Health/ ; },
mesh = {Humans ; *Alzheimer Disease/genetics/pathology/metabolism ; *Induced Pluripotent Stem Cells/metabolism/cytology ; *Neurons/metabolism/pathology ; *Mitochondria/genetics/metabolism ; *Genes, Mitochondrial ; Oxidative Stress/genetics ; Gene Expression Profiling ; Gene Ontology ; Brain/metabolism/pathology ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative condition that has become a global health challenge due to an aging world population and no available effective treatment. Mitochondrial dysfunction plays a crucial role in the development of AD due to its critical role in neuronal survival and function. However, the specific mitochondrial genes and pathways involved in AD pathogenesis remain poorly defined. In this study, we incorporated seven AD human postmortem and three AD iPSC-derived neurons (iNs) gene expression datasets to identify mitochondria-related Differentially Expressed Genes (mitoDEGs) between AD and control. The Gene Ontology (GO) analysis is conducted to investigate the AD biological mechanisms, and a random forest model is developed to assess how well the key mitoDEGs differentiate AD and control groups. Through our analysis, we identified fourteen key mitochondria related genes that show significant dysregulation in both postmortem brain tissues and iNs derived from AD patients. These genes have strong connections to oxidative stress, indicating mitochondrial dysfunction plays a crucial role in Alzheimer's disease pathology. Our study identified the key genes and pathways as promising targets for future research and therapeutic interventions, highlighting the importance of mitigating oxidative stress and restoring mitochondrial function in AD.},
}

Humans
*Alzheimer Disease/genetics/pathology/metabolism
*Induced Pluripotent Stem Cells/metabolism/cytology
*Neurons/metabolism/pathology
*Mitochondria/genetics/metabolism
*Genes, Mitochondrial
Oxidative Stress/genetics
Gene Expression Profiling
Gene Ontology
Brain/metabolism/pathology

@article {pmid41314754,
year = {2025},
author = {Jana, MK and Swarup, V and Tripathy, S and Gupta, NM and Chatla, SS and Joshi, D and Mandal, S and Giri, A and Jana, S and Narayan, M and Maiti, SB and Das, S},
title = {Future horizons: Innovation, aging, and equity.},
journal = {Progress in brain research},
volume = {297},
number = {},
pages = {427-468},
doi = {10.1016/bs.pbr.2025.08.010},
pmid = {41314754},
issn = {1875-7855},
mesh = {Humans ; *Aging ; *Precision Medicine/trends/methods ; *Neurodegenerative Diseases/therapy/diagnosis ; Artificial Intelligence ; },
abstract = {Precision medicine is on the verge of transforming the treatment of neurodegenerative diseases (NDDs) like Alzheimer's disease (AD) and Parkinson's disease (PD), in response to the intricate interactions of genetic, epigenetic, environmental, and lifestyle factors underlying disease heterogeneity. As the world's aging populations grow, with dementia cases expected to double by 2040 and the costs amounting to over €130 billion a year in Europe alone, there is an urgent need for novel strategies to stem the socioeconomic costs of NDDs. Conventional "one-drug-fits-all" strategies that depend on late-stage symptom treatment are progressively insufficient for disorders that are marked by heterogeneous molecular pathways and unpredictable clinical courses. Recent improvements in artificial intelligence (AI), multi-omics integration, and biomarker research now allow patients to be stratified into subpopulations following their genetic risk profiles, neuroimaging signatures, and fluid biomarkers (e.g., amyloid-beta, tau, α-synuclein), enabling early diagnosis and focused treatments. For example, artificial intelligence platforms such as the IHI-PROMINENT project are creating forecasting algorithms to chart disease progression and tailor treatment outcomes, and gene therapy and antisense oligonucleotides (ASOs) address precise mutations in familial AD and PD. These advances are supported by pharmacogenomics, which individualizes drug regimens according to metabolic profiles to reduce side effects and maximize efficacy. Still, translating these advances into practice has major barriers to overcome, such as large-scale biomarker validation, multi-omics standardization, and incorporating real-world evidence from digital health technologies. Aging populations only add complexity to this environment, as comorbidities like diabetes and cardiovascular diseases interact with neurodegenerative pathways, requiring system-based, holistic approaches to care. Equity is still a key challenge: differences in access to sophisticated diagnostics (e.g., PET scans, CSF examination) and expensive therapies (e.g., monoclonal antibodies, CAR-T cell therapy) threaten to worsen global health disparities. In retaliation, initiatives such as the JPND research paradigm advance remote clinical trials and telemedicine platforms for the diverse community in decentralized settings, and policies target reducing financial disincentives through risk-sharing strategies and public-private partnerships. Precision medicine in the treatment of NDDs depends on an integrated network among academia, clinics, and industry, by taking advantage of communal biobanks and AI-enabled big data analysis, for refining the drug development process and validating new targets, e.g., neuroinflammatory signaling and gut-brain axis dysfunction. Innovations, like CRISPR-mediated editing and ambient neuroimaging, have innate or potential power to personalize treatment by identifying early-stage and even pre-symptomatic patients and modulating one's lifestyle in light of genetic risk. However ethical considerations around data privacy, algorithmic bias, and informed consent for Sustained therapeutic interventions over a lifetime should guide, not lag, the transformation. With the drive toward preventive rather than delayed care, precision medicine represents a revolutionary paradigm shift in health care, and a possibility to convert NDDs from devastatingly fatal diagnoses to easily managed chronic diseases and render equitable access to innovations possible for the masses. Success will require consistent investment in translational studies, interdisciplinary training, and global regulatory harmonization to translate the promise of precision medicine into tangible improvements in the quality of life for the millions of individuals afflicted with neurodegenerative disorders.},
}

Humans
*Aging
*Precision Medicine/trends/methods
*Neurodegenerative Diseases/therapy/diagnosis
Artificial Intelligence

@article {pmid41314753,
year = {2025},
author = {Jana, MK and Mukherjee, P and Chatla, SS and Sharma, P and Mistry, J and Swarup, V and Srivastava, AK and Das, S and Gupta, NM and Ahuja, A and Samanta, S and Narayan, M},
title = {Global case studies and collaborative frameworks.},
journal = {Progress in brain research},
volume = {297},
number = {},
pages = {377-426},
doi = {10.1016/bs.pbr.2025.08.013},
pmid = {41314753},
issn = {1875-7855},
mesh = {Humans ; *Neurodegenerative Diseases/therapy/diagnosis ; *Biomedical Research ; *International Cooperation ; },
abstract = {As neurodegenerative diseases (NDDs) like Alzheimer's and Parkinson's continue to rise globally, the need for cross-border collaboration in research and treatment has never been more critical. This chapter explores prominent global case studies and collaborative frameworks that exemplify how united efforts are transforming the landscape of NDD research. By pooling expertise, data, and resources, international initiatives are accelerating discoveries in early diagnosis, biomarker identification, and personalized therapies. Highlighting landmark consortia such as the Alzheimer's Disease Neuroimaging Initiative (ADNI) (n.d.), Parkinson's Progression Markers Initiative (PPMI), and emerging multi-omics collaborations, the chapter illustrates how these partnerships overcome the complexity and heterogeneity of NDDs. It delves into technological innovations like artificial intelligence, blockchain data sharing, and real-time patient monitoring, which empower researchers and clinicians to connect genetic, environmental, and lifestyle factors in a holistic manner. Ethical considerations and data privacy frameworks are underscored as pivotal to fostering trust among participants and bridging disparities between regions with varying access to precision medicine. The chapter also sheds light on successful public-private partnerships and patient-focused global networks that place individuals at the center of discovery and care. Challenges such as standardizing protocols across countries, navigating legal frameworks, and securing sustainable funding are discussed alongside future directions for expanding collaborative reach. Ultimately, this comprehensive overview conveys the unprecedented promise held by global cooperation in combating neurodegenerative diseases-offering hope for improved diagnostics, innovative treatments, and enhanced quality of life for millions worldwide.},
}

Humans
*Neurodegenerative Diseases/therapy/diagnosis
*Biomedical Research
*International Cooperation

@article {pmid41314749,
year = {2025},
author = {Priyanka, S and Manjari, T and Hemalatha, S and Ambika, S and Yılmaz, B and Aktürk, B and Arısan, ED and Kumari, A and Manojkumar, Y},
title = {Precision therapeutics for Alzheimer's disease.},
journal = {Progress in brain research},
volume = {297},
number = {},
pages = {247-276},
doi = {10.1016/bs.pbr.2025.08.011},
pmid = {41314749},
issn = {1875-7855},
mesh = {Humans ; *Alzheimer Disease/therapy/genetics/drug therapy ; *Precision Medicine/methods ; Animals ; },
abstract = {Despite extensive research, Alzheimer's disease (AD) a progressive neurodegenerative disorder marked by cognitive decline, neuronal loss, and the build-up of amyloid-beta plaques and tau tangles continues to lack effective treatments. Precision medicine presents a promising shift by customizing interventions to an individual's genetic, molecular, and lifestyle profile. This chapter explores key advancements in precision therapeutics for AD, including biomarker-driven therapies, pharmacogenomics, and targeted disease-modifying agents such as monoclonal antibodies. Recent innovations, including RNA-based therapeutics, stem cell approaches, and CRISPR-mediated gene editing, are also discussed. While precision medicine holds immense promise, challenges in clinical translation, patient stratification, and regulatory pathways must be addressed. By bridging cutting-edge research with clinical applications, this chapter provides insights into the evolving landscape of individualized treatment strategies for AD.},
}

Humans
*Alzheimer Disease/therapy/genetics/drug therapy
*Precision Medicine/methods
Animals

@article {pmid41314745,
year = {2025},
author = {Fatima, S and Tiwari, S and Siddiqi, B and Quadri, SN and Abdin, MZ},
title = {Biomarkers: From early detection to treatment personalization.},
journal = {Progress in brain research},
volume = {297},
number = {},
pages = {131-153},
doi = {10.1016/bs.pbr.2025.08.008},
pmid = {41314745},
issn = {1875-7855},
mesh = {Humans ; *Biomarkers/metabolism ; *Neurodegenerative Diseases/diagnosis/therapy/metabolism ; *Precision Medicine/methods ; Early Diagnosis ; },
abstract = {Neurodegenerative disorders (NDs), such as Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), present increasing issues associated with the unavoidable aging of the world's population. These challenges are further highlighted by the socioeconomic consequences of these diseases. The identification and use of biomarkers for prompt diagnosis, careful observation, and efficient treatment approaches is essential to overcoming these obstacles. The primary methods for diagnosing neurodegenerative illnesses are invasive procedures like lumbar punctures to measure CSF fluid or functional brain imaging methods. Biomarkers for underlying proteinopathy in blood serum and cerebral fluid have been the focus of recent biological research, particularly in vivo. With their ability to provide novel pathways for early detection, illness progression tracking, and individualized treatment plans, biomarkers have become essential instruments in precision medicine. The classification of biomarkers including fluid, digital imaging, and molecular biomarkers is examined in this chapter, with an emphasis on their function in neurodegenerative diseases. In neurodegenerative illnesses and the aging brain, tau, amyloid-β, α-synuclein, and TDP-43 are commonly seen to be deposited together rather than separately. These may be disregarded, and it might be challenging to determine their clinicopathological significance. An overview of illness pathophysiology, diagnostic implications, and the most recent molecular and ultrastructural categories for neurodegenerative disorders are given in this chapter. Addressing these issues through interdisciplinary research and technological advancements will be crucial for the future of biomarker-driven precision medicine. This chapter provides an in-depth overview of the evolving landscape of biomarkers and their transformative impact on the early detection and personalized treatment of neurodegenerative diseases.},
}

Humans
*Biomarkers/metabolism
*Neurodegenerative Diseases/diagnosis/therapy/metabolism
*Precision Medicine/methods
Early Diagnosis

@article {pmid41314744,
year = {2025},
author = {Gunasekaran, B and Arifin, AH and Yu, WH and Hanafi, S and Rao, KDK and Salvamani, S},
title = {Precision medicine in neurodegenerative diseases: From research to clinical practice.},
journal = {Progress in brain research},
volume = {297},
number = {},
pages = {1-52},
doi = {10.1016/bs.pbr.2025.08.006},
pmid = {41314744},
issn = {1875-7855},
mesh = {Humans ; *Precision Medicine/methods ; *Neurodegenerative Diseases/therapy/genetics/diagnosis ; Biomarkers ; },
abstract = {The chapter outlines how precision medicine is reshaping the way neurodegenerative diseases (NDs) which includes Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD) are understood, diagnosed, and treated. It discusses the limitations of current therapies, which mainly address symptoms without altering disease progression. Genetic and molecular factors that influence disease development are described, including distinctions between familial and sporadic forms. The chapter also covers the roles of epigenetic changes, gene expression, protein dysfunction, mitochondrial DNA, and non-coding RNAs in NDs. Biomarkers in blood and cerebrospinal fluid, along with imaging techniques and digital tools, are presented as key elements in early diagnosis and disease monitoring. Patient stratification based on clinical features, molecular profiles, and biomarkers helps guide treatment decisions and improve outcomes. The chapter reviews ongoing developments in genotype-based drug design, gene therapy, pharmacogenomics, and personalized lifestyle strategies. Clinical case studies show how these approaches are being used in practice. The chapter also discusses challenges in applying precision medicine, such as trial design, data integration, unequal access, and regulatory hurdles. Finally, it highlights the future tools like single-cell transcriptomics, digital twins, and global research collaborations that aim to bring precision approaches into everyday care.},
}

Humans
*Precision Medicine/methods
*Neurodegenerative Diseases/therapy/genetics/diagnosis
Biomarkers

@article {pmid41314580,
year = {2025},
author = {Wang, X and Wang, D and Liu, J and Han, F and Liang, P and Yang, J and Xu, W and Ma, J and Wu, Y and An, X and Xue, Y and Chen, H and Zeng, L and Qu, Y and Ai, J},
title = {Systemic delivery of liposome-loaded microRNA-195 ameliorates spatial memory impairment in a rat model of chronic cerebral hypoperfusion.},
journal = {International journal of biological macromolecules},
volume = {},
number = {},
pages = {149290},
doi = {10.1016/j.ijbiomac.2025.149290},
pmid = {41314580},
issn = {1879-0003},
abstract = {Chronic cerebral hypoperfusion (CCH), a subclinical state underlying mild cognitive impairment (MCI), triggers multiple pathological changes associated with Alzheimer's disease (AD) and vascular dementia (VaD), including amyloid-β (Aβ) deposition, tau phosphorylation, microglial activation and neural circuit dysfunction. Developing multitarget therapeutics to effectively prevent the transition from MCI to AD and/or VaD remains an urgent challenge. Herein, we engineered a brain-targeted dual-modified PEGylated nanoliposome (LipTM@miR-195), incorporating mannose (MAN) and the trans-activating protein of HIV type 1 (TAT), which encapsulates polyethyleneimine (PEI) complesed microRNA-195 (miR-195). In a CCH rat model, tail-vein administration of LipTM@miR-195 (0.112 mg/kg) efficiently crossed the blood-brain barrier (BBB) without detectable side effects. Treatment reversed CCH-induced spatial learning and memory deficits, rescued neural circuit dysfunction, and suppressed elevated APP, BACE1, AT8 and CD68 levels. Collectively, these findings provide compelling evidence that LipTM@miR-195 nanoliposome holds therapeutic potential for CCH-induced cognitive impairment, thereby preventing the progression from MCI to AD and/or VaD.},
}

@article {pmid41314098,
year = {2025},
author = {Ye, M and Kim, JS and Shim, I},
title = {CB1 receptor activation and inhibition differentially modulate cognitive deficits and neuropathology in 3xTg-AD mice.},
journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie},
volume = {193},
number = {},
pages = {118818},
doi = {10.1016/j.biopha.2025.118818},
pmid = {41314098},
issn = {1950-6007},
abstract = {Alzheimer's disease (AD) is characterized by amyloid-β (Aβ) deposition, tau hyperphosphorylation, neuroinflammation, oxidative stress, and progressive neuronal loss. The endocannabinoid system regulates synaptic function, inflammation, and redox homeostasis through cannabinoid receptor type 1 (CB1). This study aimed to determine whether pharmacological activation or inhibition of the CB1 receptor differentially modulates Alzheimer's disease-related pathology. 3xTg-AD mice received weekly intraperitoneal injections of the CB1 agonist ACEA (1 mg/kg) or the inverse agonist AM251 (1 mg/kg) from 6 to 12 months of age. Cognitive function was assessed using the Morris Water Maze (MWM) and Y-maze, while hippocampal tissues were analyzed for Aβ, p-Tau, glial markers (GFAP, Iba-1), cytokines (IL-1β, IL-10), oxidative stress markers (SOD, GSH, MDA), and neuronal viability (NeuN). Cerebral glucose metabolism was evaluated using [1] [8]F-FDG positron emission tomography (PET). ACEA administration reduced tau phosphorylation, glial activation, IL-1β expression, and oxidative stress, while increasing IL-10 levels, neuronal preservation, and cerebral glucose metabolism. AM251 treatment aggravated tau pathology, neuroinflammation, oxidative imbalance, and cognitive impairment. Double immunofluorescence demonstrated CB1 receptor colocalization with both Iba-1-positive microglia and GFAP-positive astrocytes, with CB1 predominantly localized to microglia, suggesting a microglia-dependent mechanism underlying CB1-mediated neuroprotection. Aβ levels were not affected by either treatment. Chronic CB1 receptor activation attenuates tau-associated pathology and metabolic dysfunction in 3xTg-AD mice, indicating the therapeutic relevance of CB1 signaling modulation in neurodegenerative disorders.},
}

@article {pmid41313999,
year = {2025},
author = {Pei, Z and Zhu, L and Ren, H and Liu, Y and Shi, X and Lin, Y and Wang, J and Li, P and Wang, P and Ji, Y and Zhou, Y and Tang, X and Jiang, X and Tong, X and Guo, Y},
title = {EEG-based stratification in Alzheimer's disease: Cognitive progression, pathological marker associations, and therapeutic interventions.},
journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology},
volume = {182},
number = {},
pages = {2111440},
doi = {10.1016/j.clinph.2025.2111440},
pmid = {41313999},
issn = {1872-8952},
abstract = {OBJECTIVE: Clinical cognitive and pathological marker stratification systems have evolved separately, causing mismatches that limit their clinical use. This study retrospectively validated the link between EEG and clinical symptoms, pathological markers, and the therapeutic efficacy of repetitive transcranial magnetic stimulation (rTMS).

METHODS: This multicenter study involved 308 Alzheimer's patients (AD), 176 with Parkinson's (PD), and 181 normal controls. Resting-state EEG were analyzed to identify four oscillation modes. An EEG-based cognitive risk system was created and validated, also evaluating its effect on rTMS therapy effectiveness.

RESULTS: EEG oscillation changes correlated with cognitive decline, revealing distinct brain network disruptions in AD and PD. These oscillation changes were associated with AD biomarkers, particularly tau hyperphosphorylation. Multicenter validation showed an 83% concordance with the Clinical Dementia Rating Scale, and EEG stratification enhanced rTMS therapeutic efficacy.

CONCLUSIONS: This study showed that EEG-based stratification can assess cognitive function, track disease progression, identify key intervention periods, and improve patient selection for better treatment outcomes in clinical settings.

SIGNIFICANCE: This study demonstrates that EEG can connect disease processes to clinical symptoms at a molecular level, offering a unified framework for improved dementia management. This method allows for dynamic monitoring and precise neuromodulation, enhancing personalized care for neurodegenerative diseases.},
}

@article {pmid41313889,
year = {2025},
author = {Jelčić, A and Talić, S and Odak, I and Mlakić, M and Lasić, Z and Roca, S and Šagud, I and Bruketa, T and Bosnar, M and Barić, D and Škorić, I},
title = {Exploring the selective butyrylcholinesterase inhibition potential of phenol carbamates: Experimental and computational study.},
journal = {European journal of medicinal chemistry},
volume = {302},
number = {Pt 3},
pages = {118375},
doi = {10.1016/j.ejmech.2025.118375},
pmid = {41313889},
issn = {1768-3254},
abstract = {A series of fourteen novel phenol carbamates was synthesized and evaluated as potential selective butyrylcholinesterase (BChE) inhibitors targeting cholinergic dysfunction in Alzheimer's disease (AD). The compounds were prepared efficiently from resveratrol analogs via a Wittig reaction followed by carbamoylation, and their structures were confirmed by NMR, MS, and HRMS analyses. All derivatives were screened for inhibitory activity against acetylcholinesterase (AChE) and BChE using a modified Ellman method. None of the compounds inhibited AChE, whereas all selectively inhibited BChE, with IC50 values ranging from 0.045 to 6.840 μM. The most potent inhibitor, compound 13, bearing a pyrrolidine moiety, exhibited an IC50 value of 0.045 μM, outperforming the reference drug galantamine by more than two orders of magnitude. Molecular docking and dynamics simulations confirmed strong π-π and alkyl-π interactions between the ligands and the enzyme's active site, accounting for their high affinity and selectivity. In silico ADME(T) analysis predicted excellent intestinal absorption, blood-brain barrier penetration, and low cytotoxicity, while minor genotoxicity alerts were observed for a few derivatives. In vitro cytotoxicity assays in HepG2 cells confirmed the absence of toxicity at concentrations up to 30 μM. These results highlight methoxy-substituted phenol carbamates, particularly compound 13, as promising lead structures for the design of selective BChE inhibitors and potential therapeutic agents for the treatment of AD.},
}

@article {pmid41313642,
year = {2025},
author = {Mangalmurti, A and Zengeler, KE and Hollis, A and Golden, E and Riddlemoser, G and Lukens, JR},
title = {Microglial CLEC7A restrains amyloid beta plaque pathology in a mouse model of Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {11},
pages = {e70943},
doi = {10.1002/alz.70943},
pmid = {41313642},
issn = {1552-5279},
support = {ADSF-21-816651/ALZ/Alzheimer's Association/United States ; /NH/NIH HHS/United States ; R01AG071996/AG/NIA NIH HHS/United States ; R01AG087406/AG/NIA NIH HHS/United States ; RF1AG078684/AG/NIA NIH HHS/United States ; //Cure Alzheimer's Fund/ ; //The Steven A Newman AD Award/ ; //Rick Sharp Foundation/ ; //Harrison Family Foundation/ ; T32GM007267//Medical Scientist Training Program/ ; T32AI007496//Immunology Training Program/ ; T32AI007496//National Institute of Allergy and Infectious Diseases/ ; T32GM156694/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; *Alzheimer Disease/pathology/metabolism/genetics ; *Plaque, Amyloid/pathology/metabolism ; Disease Models, Animal ; *Microglia/metabolism/pathology ; *Lectins, C-Type/metabolism/genetics ; Mice ; Mice, Transgenic ; Mice, Knockout ; Macrophages/metabolism ; Amyloid beta-Peptides/metabolism ; Humans ; Brain/pathology/metabolism ; },
abstract = {INTRODUCTION: CLEC7A is a surface receptor that is highly upregulated on microglia in many Alzheimer's disease (AD) models. Little is known about the role that microglial CLEC7A signaling plays in AD-related pathogenesis.

METHODS: We utilized an inducible, central nervous system (CNS) macrophage-specific knockout of Clec7a to evaluate the role of CLEC7A in the 5xFAD mouse model of AD at 5 months of age. We used immunofluorescence microscopy, single-nuclei RNA sequencing, along with biochemical assays, to evaluate plaque burden, microglial activity, and neuronal health.

RESULTS: CNS macrophage-targeted deletion of CLEC7A in 5xFAD mice led to a twofold increase in plaque burden, exacerbated neuritic dystrophy, and altered the expression of neuronal health genes, but did not appreciably impact microglial activation, plaque engulfment, or disease-associated microglia acquisition.

DISCUSSION: These findings identify protective roles for CLEC7A in AD-related amyloidosis and suggest that CLEC7A-targeting therapeutics may offer promising strategies for treatment of AD.

HIGHLIGHTS: Conditional loss of CLEC7A in central nervous system (CNS) macrophages of 5xFAD mice results in increased amyloid beta deposition. Loss of CLEC7A does not alter the disease-associated microglia transcriptional program or affect the recruitment of microglia to plaque surfaces. Exacerbation of amyloid deposition with loss of CNS-macrophage CLEC7A is associated with worsened neuronal health highlighted by increased neuritic dystrophy.},
}

Animals
*Alzheimer Disease/pathology/metabolism/genetics
*Plaque, Amyloid/pathology/metabolism
Disease Models, Animal
*Microglia/metabolism/pathology
*Lectins, C-Type/metabolism/genetics
Mice
Mice, Transgenic
Mice, Knockout
Macrophages/metabolism
Amyloid beta-Peptides/metabolism
Humans
Brain/pathology/metabolism

@article {pmid41312814,
year = {2025},
author = {Akpınar, O and Nazıroğlu, M},
title = {Glutathione and TRPM2 Inhibition Reduce Amyloid-Beta and Lipopolysaccharide-Induced Apoptosis, Inflammation, and Oxidative Stress in Microglial Cells.},
journal = {Cell biology international},
volume = {},
number = {},
pages = {},
doi = {10.1002/cbin.70109},
pmid = {41312814},
issn = {1095-8355},
support = {//This study was supported by the Scientific Research Projects Coordination Unit (BAP) of Süleyman Demirel University (project number: TDK-2021-8387). Project owner was Mustafa Nazıroğlu./ ; },
abstract = {Microglia cells impacted by inflammation and Alzheimer's disease produce toxic reactive oxygen species (ROS), emit signaling molecules, and death as a result of microglia being active due to excessive Ca[2+] entering the cells. The TRPM2 channel plays a crucial role in Ca[2+] permeability, inflammation, ROS, and apoptosis changes in the BV2 microglia cells, while glutathione (GSH) treatment reduces the changes through TRPM2 inhibition. However, the effect of TRPM2 inhibitors and GSH treatment on oxidative stress, inflammation, and apoptotic values in BV2 microglia cells activated with LPS and amyloid-beta (Aβ) has not been investigated yet. The study aimed to assess the effects of TRPM2 inhibition and GSH treatment on the values in BV2 cells activated with LPS and Aβ. BV2 cells were divided into five groups: control (CNT), LPS, Aβ, Aβ + LPS, and Aβ + LPS + GSH. Increased levels of inflammation biomarkers (TNF-α, IL-1β, and IL-6), intracellular Ca[2+] level, cytosolic ROS, mitochondrial membrane dysfunction, cell death, apoptosis, caspases (caspase-3, -8, and -9), and TRPM2 current density were observed in the cells stimulated with LPS and Aβ. These values increased more when LPS and Aβ were incubated together. However, these apoptotic, inflammatory, and oxidant levels decreased in cells treated with GSH and TRPM2 blockers. In conclusion, the involvement of TRPM2 stimulation was demonstrated on Aβ and LPS-induced Ca[2+] entry, oxidative stress, inflammation, and apoptosis parameters in microglia cells. TRPM2 inhibition by GSH treatment seems to be a potential source for the prevention of Aβ and LPS-induced oxidative stress, apoptosis, and inflammation.},
}

@article {pmid41312794,
year = {2025},
author = {Healy, M and Thomas, S and Brodtmann, A},
title = {Magnetic resonance imaging eligibility for anti-amyloid monoclonal antibody treatment for Alzheimer disease: a single-centre retrospective review for service planning.},
journal = {Internal medicine journal},
volume = {},
number = {},
pages = {},
doi = {10.1111/imj.70254},
pmid = {41312794},
issn = {1445-5994},
}

@article {pmid41312566,
year = {2025},
author = {Kwinta, R and Morawiec, N and Bączyk, J and Kubicka-Bączyk, K and Adamczyk-Sowa, M},
title = {Aging immunity - the role of T and B cells in neurological disorders among older adults.},
journal = {Neurologia i neurochirurgia polska},
volume = {},
number = {},
pages = {},
doi = {10.5603/pjnns.106498},
pmid = {41312566},
issn = {0028-3843},
abstract = {INTRODUCTION: Immunosenescence is a natural process of immune system aging, which leads to significant changes in the functioning of both innate and adaptive immunity. Alterations in T and B lymphocytes can significantly impact the progression of neurological diseases including multiple sclerosis (MS), Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS).

STATE OF THE ART: Immunosenescence affects T and B cell subsets, reducing their proliferative capacity and altering cytokine profiles. In MS, these changes promote disease progression and diminish responses to immunomodulatory therapies. In AD and PD, dysfunctional T and B cells contribute to sustained neuroinflammation, exacerbating neurodegeneration. ALS is similarly associated with altered adaptive immunity.

CLINICAL IMPLICATIONS: Recognizing how immunosenescent T and B cells contribute to disease in older adults is crucial for refining treatment strategies. These age-related immune changes may explain varied responses to therapies and highlight the need for novel approaches targeting the aged immune system in neurodegenerative diseases.

FUTURE DIRECTIONS: Future research should focus on identifying the mechanisms by which immunosenescent lymphocytes modulate neuroinflammation and neurodegeneration in aging populations. Novel biomarkers and immunomodulatory therapies tailored to older adults could significantly improve outcomes in patients with neurological diseases.},
}

@article {pmid41311387,
year = {2025},
author = {Zhou, Y and Wang, Y and Yang, H and Zhang, C and Meng, J and Zhang, L and Li, K and Huang, LL and Zhang, X and Luo, H and Zhang, Y},
title = {Sorafenib promotes the E3 ubiquitin ligase FBXW7 to increase tau degradation and ameliorate tauopathies.},
journal = {Acta pharmaceutica Sinica. B},
volume = {15},
number = {11},
pages = {5817-5831},
pmid = {41311387},
issn = {2211-3835},
abstract = {Tauopathies, including Alzheimer's disease (AD), are a series of neurodegenerative diseases characterized by pathological accumulation of the microtubule-associated protein tau. Since the abnormal modification and deposition of tau in nerve cells are crucial for tauopathy etiology, methods for reducing tau levels, such as promoting tau degradation, may become effective strategies for disease treatment. Herein, we identified that sorafenib significantly reduced total tau and phosphorylated tau levels through screening FDA-approved drugs. We showed that sorafenib treatment attenuated cognitive deficits and tau pathologies in PS19 tauopathy model mice. Mechanistically, we found that sorafenib inhibited multiple kinases involved in tau phosphorylation and promoted autophagy. Importantly, we further demonstrated that sorafenib also promoted the expression of the E3 ubiquitin ligase FBXW7, which could bind tau and mediate tau degradation through the ubiquitin-proteasome pathway. Finally, we showed that FBXW7 expression decreased in the brains of AD patients and tauopathy model mice, and that overexpression of FBXW7 in the hippocampus attenuated cognitive deficits and tau pathologies in PS19 mice. These results suggest that sorafenib may be a promising treatment option for tauopathies by promoting tau degradation and reducing tau phosphorylation, and that targeting FBXW7 could also serve as an alternative therapeutic strategy for tauopathies.},
}

@article {pmid41311386,
year = {2025},
author = {Zhao, Y and Liu, X and Yang, S and Wang, J and Wu, D and Bu, Y and Xie, X},
title = {Electrochemical biosensors with right-side-out-oriented cell membrane coating for the evaluation of AChE inhibitors as potential anti-Alzheimer's disease agents.},
journal = {Acta pharmaceutica Sinica. B},
volume = {15},
number = {11},
pages = {5988-6000},
pmid = {41311386},
issn = {2211-3835},
abstract = {Biosensors based on acetylcholinesterase (AChE) are crucial for early diagnosis, less invasive treatment, and drug evaluation of Alzheimer's disease (AD). However, existing technologies often suffer from enzyme conformational changes, leading to altered activity and loss and reduced sensor efficacy. To address this challenge, we developed a novel right-side-out-oriented red blood cell membrane-coated electrochemical biosensors (ROCMCBs) to evaluate AChE inhibitors from traditional Chinese medicines (TCMs) as potential anti-AD agents. The developed right-side-out-oriented coating based on immunoaffinity not only fully exposed the binding sites of AChE on the cell membrane but also ensured its conformation and stability as a peripheral membrane-anchoring protein, which was conducive to maintaining its biological activity and producing optimal interaction with drugs. At the same time, the biosensors exhibited a satisfactory sensitivity (limit of detection = 0.41 pmol/L). Ultimately, six potentially active compounds against AD (baicalin, geniposide, gastrodin, berberine, rhynchophylline, and senkyunolide A) were rapidly identified and evaluated from TCMs. This project provides a promising strategy for developing cell membrane-coated electrochemical biosensors. The application of cell membrane-coated electrochemical biosensors with well-defined cell membrane orientation further expands new perspectives and methods for AChE-targeted anti-AD research.},
}

@article {pmid41311299,
year = {2025},
author = {Pini, L and Allali, G and Imbimbo, BP and Germani, M and Corbetta, M},
title = {Brain connectivity as a new target for Alzheimer's disease therapy?.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awaf404},
pmid = {41311299},
issn = {1460-2156},
abstract = {The recent introduction of immunotherapeutic agents targeting amyloid-β (Aβ) has advanced the pharmacological treatment of Alzheimer's disease (AD). Although several anti-Aβ antibodies have dramatically reduced cerebral amyloid plaques, this has not translated into major cognitive or clinical benefits, thus questioning the clinical relevance of these biomarker changes. Indeed, there is an ongoing debate over whether amyloid reduction alone constitutes sufficient evidence of disease modification to justify regulatory approval. Against this backdrop, we propose a third pathway that transcends the binary framework of molecular versus clinical end points by positioning brain connectivity as a system-level intermediate phenotype. This approach is supported by a growing body of evidence. Alterations in brain networks are early, sensitive, and modifiable markers of AD pathology. Connectivity metrics capture the dynamic interplay between genetic and environmental factors, offering a unified model of disease. Advances in precision medicine, such as individualized connectivity 'fingerprints' and the emergence of digital twins, further position brain connectivity as a powerful platform for therapeutic innovation. We argue that adopting brain network analysis as a key outcome measure enables a shift beyond isolated biomarker achievements toward a more integrated, biologically grounded, and clinically meaningful framework for disease modification in AD, bridging the gap between molecular advances and real-world impact.},
}

@article {pmid41311279,
year = {2025},
author = {Garland, H and Jacobson, M and Xu, S and Zissimopoulos, J},
title = {A scoping review of population-based dementia registries: advancing research, care, and policy.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {11},
pages = {e70938},
doi = {10.1002/alz.70938},
pmid = {41311279},
issn = {1552-5279},
mesh = {Humans ; *Registries ; *Dementia/therapy/epidemiology ; *Health Policy ; },
abstract = {Despite their value for public health, research, and care, population-based registries for Alzheimer's disease and related dementias (ADRD) remain limited. We conducted a scoping review of dementia registry studies through December 2023 and identified population-based dementia registries in Organisation for Economic Co-operation and Development countries. We characterized their structure and scope, assessed key themes, and developed recommendations for registry development. We identified 21 population-based dementia registries from a review of 235 publications. These registries help fill gaps in dementia research by providing longitudinal data, improving case identification, and standardizing outcomes for clinical and policy use. However, many registries lack data on healthcare use and caregiving and have limited geographical coverage, thereby reducing their ability to inform research and public health efforts to address dementia burden in an era of rapidly evolving dementia diagnostics and treatments. As dementia cases rise and advancements in prevention, detection, and treatment accelerate, population-based registries are essential for generating real-world evidence to improve dementia care, policy, and outcomes. HIGHLIGHTS: This scoping review identified 21 population-based dementia registries across OECD countries, highlighting the current landscape and structural gaps. Registries provide critical longitudinal data and standardization for research and policy but often lack information on healthcare use, caregiving, and broad geographic representation. With rising dementia rates and evolving treatments, population-based registries are essential for producing real-world evidence to strengthen care, research, and public health planning.},
}

Humans
*Registries
*Dementia/therapy/epidemiology
*Health Policy

@article {pmid41311076,
year = {2025},
author = {Li, X and Zhang, Y and Gu, Y and Chen, N and Qian, X and Zhang, P and Hao, J and Wang, F},
title = {[Association between Tau protein deposition and brain metabolites: N-acetylaspartate and creatine as potential biomarkers for advanced Alzheimer's disease].},
journal = {Nan fang yi ke da xue xue bao = Journal of Southern Medical University},
volume = {45},
number = {11},
pages = {2350-2357},
doi = {10.12122/j.issn.1673-4254.2025.11.07},
pmid = {41311076},
issn = {1673-4254},
mesh = {Humans ; *Alzheimer Disease/metabolism/diagnostic imaging ; *Aspartic Acid/analogs & derivatives/metabolism ; *tau Proteins/metabolism ; *Creatine/metabolism ; *Brain/metabolism ; Biomarkers/metabolism ; Positron-Emission Tomography ; Male ; Female ; Proton Magnetic Resonance Spectroscopy ; Choline/metabolism ; Aged ; Middle Aged ; },
abstract = {OBJECTIVES: To investigate the associations between Tau protein deposition and brain biochemical metabolites detected by proton magnetic resonance spectroscopy ([1]H-MRS) in patients with advanced Alzheimer's disease (AD).

METHODS: From April, 2022 to December, 2024, 64 Tau-positive AD patients and 29 healthy individuals underwent [18]F-APN-1607 PET/MR and simultaneously acquired multi-voxel [1]H-MRS in the Department of Nuclear Medicine, Nanjing First Hospital. Visual analysis and voxel-based analysis of PET/MR data were performed to investigate the Tau protein deposition patterns in AD patients. Valid voxels within the [1]H-MRS field of view were selected, and their standardized uptake value ratio (SUVr) in PET and metabolite levels of N-acetylaspartate (NAA), choline (Cho), creatine (Cr), NAA/Cr, and Cho/Cr were recorded. The Tau-positive (Tau[+]) voxels and Tau-negative (Tau[-]) voxels of the AD patients were compared for PET and [1]H-MRS parameters, and the correlations between the metabolites and Tau PET SUVr within Tau[+] voxels were analyzed.

RESULTS: Significant Tau protein deposition were observed in the AD patients, involving mainly the bilateral frontal lobes (30.07%), parietal lobes (29.96%), temporal lobes (21.07%), and occipital lobes (15.89%). A total of 1422 valid voxels in AD group (including 994 Tau[+] and 428 Tau[-] voxels) and 814 voxels in the control group were selected. The AD patients showed significantly decreased NAA level and increased SUVr compared with the control group (P<0.05). Subgroup analyses revealed that Tau[+] voxels had higher SUVr and lower Cr and Cho/Cr than Tau[-] voxels (P<0.05). Compared with the control group, Tau[+] voxels exhibited higher SUVr and lower Cr (P<0.05), while Tau[-] voxels showed lower NAA (P=0.004). No significant differences were found in Cho or NAA/Cr among the subgroups (P>0.05). Within Tau[+] voxels, NAA, Cho, and Cr were negatively correlated with SUVr (P<0.001).

CONCLUSIONS: The patients with progressive AD have significant Tau protein deposition in the brain, which is correlated with alterations in metabolite levels. Decreased NAA is more prominent in early or pre-tau deposition stages, while Cr changes is more significant in the regions with Tau protein deposition, suggesting the potential of NAA and Cr as biomarkers for Tau protein deposition in AD for disease monitoring and treatment evaluation.},
}

Humans
*Alzheimer Disease/metabolism/diagnostic imaging
*Aspartic Acid/analogs & derivatives/metabolism
*tau Proteins/metabolism
*Creatine/metabolism
*Brain/metabolism
Biomarkers/metabolism
Positron-Emission Tomography
Male
Female
Proton Magnetic Resonance Spectroscopy
Choline/metabolism
Aged
Middle Aged

@article {pmid41309432,
year = {2025},
author = {Bai, N and Liu, S and Wei, J and Zheng, B and Wang, W and Li, X and Yang, J and Song, X and Wang, L and Yi, F and Cao, L},
title = {Sirtuins in Alzheimer's disease: mechanistic insights and therapeutic opportunities.},
journal = {Trends in pharmacological sciences},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.tips.2025.10.016},
pmid = {41309432},
issn = {1873-3735},
abstract = {Alzheimer's disease (AD) is an irreversible neurodegenerative disorder characterized by progressive cognitive decline and complex neuropathology. Its main features include amyloid-β (Aβ) plaques, tau neurofibrillary tangles (NFTs), and neuroinflammation. Current therapies provide only limited symptomatic relief and cannot stop disease progression, highlighting the urgent need for disease-modifying strategies. Recent research has revealed multiple roles of sirtuins in AD pathology, positioning them as promising therapeutic targets. Studies using small-molecule compounds to target sirtuins, in both cellular and animal models and clinical analyses of AD patients, demonstrate their therapeutic potential. This review discusses the distinct roles of individual sirtuin isoforms in AD pathogenesis and evaluates the therapeutic evidence for small-molecule sirtuin modulators.},
}

@article {pmid41309190,
year = {2025},
author = {Shah, A and Karthikeyan, T and Hashem, S and Kumar, R and Bhat, AA and Macha, MA},
title = {Protein misfolding and neurodegeneration: Mechanisms, implications, and therapeutic strategies.},
journal = {Advances in protein chemistry and structural biology},
volume = {148},
number = {},
pages = {135-177},
doi = {10.1016/bs.apcsb.2025.08.012},
pmid = {41309190},
issn = {1876-1631},
mesh = {Humans ; *Protein Folding ; *Neurodegenerative Diseases/metabolism/pathology/drug therapy/therapy ; *Proteostasis Deficiencies/metabolism/pathology/therapy ; Animals ; Proteostasis ; },
abstract = {Protein misfolding and aggregation play a pivotal role in the development of neurodegenerative diseases such as Alzheimer's, Parkinson's, Huntington's disease, and other related disorders. Proper protein folding is essential for cellular function, but due to the complexity of the folding process and external factors like genetic mutations, oxidative stress, and aging, misfolding is inevitable. These misfolded proteins often aggregate into toxic forms that disrupt cellular processes, leading to neuronal damage and cognitive decline. This chapter provides a comprehensive overview of molecular mechanisms behind protein misfolding, highlighting how these abnormal structures contribute to neurodegeneration. It also explores the role of the proteostasis network and its therapeutic potential in alleviating these processes. Focusing on multitarget therapeutic strategies, the chapter offers insights into promising approaches for addressing the root causes of neurodegenerative diseases while identifying key research gaps that could shape future treatment developments. By blending current knowledge with emerging therapeutic directions, this chapter provides a comprehensive and engaging perspective on combating the challenges of protein misfolding in neurodegeneration.},
}

Humans
*Protein Folding
*Neurodegenerative Diseases/metabolism/pathology/drug therapy/therapy
*Proteostasis Deficiencies/metabolism/pathology/therapy
Animals
Proteostasis

@article {pmid41307609,
year = {2025},
author = {Katayama, S and Tsujimoto, M and Suzuki, K and Ueda, K and Shimoura, K and Suo, S and Hatakeyama, N},
title = {Care Partners' Perceptions of Amyloid-Targeting Therapy and Treat‑to‑Clearance for Alzheimer's Disease in Japan: A Qualitative Study.},
journal = {Neurology and therapy},
volume = {},
number = {},
pages = {},
pmid = {41307609},
issn = {2193-8253},
abstract = {INTRODUCTION: Donanemab has been developed as an amyloid-targeting therapy (ATT) for mild cognitive impairment (MCI) and mild dementia due to Alzheimer's disease (AD). In registration trials involving donanemab, a treat‑to‑clearance approach was used, in which patients discontinued ATT when amyloid plaque levels decreased below a predefined threshold, which differs from previously available symptomatic treatments for AD. Our study explored care partners' perceptions regarding ATT and treat‑to‑clearance.

METHODS: This was a cross-sectional, qualitative interview study. Care partners of individuals with MCI or mild dementia due to AD participated in online semi-structured interviews about their perceptions regarding the impact of MCI or mild dementia diagnoses due to AD, the burden of supporting, and use/cessation of ATT. The qualitative data from the interviews were analyzed using a thematic approach.

RESULTS: The participants were 22 care partners (5 male/17 female), and their median age was 59 (range 35-81) years. The most common relationships between care partners and the individuals with AD were child (50.0%) and spouse/partner (45.5%); 68.2% of the care partners lived with the individuals with AD. Thematic analysis identified three major classifications (Thoughts regarding therapy; Treat‑to‑clearance; and Burdens of support), along with 15 themes and five sub-themes. Care partners expressed experiencing mental burden and time constraints, while treat‑to‑clearance could save care partners' time by reducing hospital waiting time and alleviating financial burden. Confirming the clearance of amyloid β plaques provided care partners with a sense of relief, while they remained concerned about the potential progression of AD symptoms and sought follow-up care after stopping treatment.

CONCLUSIONS: These results suggest that providing clear explanations and facilitating shared decision-making when introducing ATT, as well as introducing follow-up care and long-term evidence after stopping treatment, are needed.},
}

@article {pmid41307478,
year = {2025},
author = {Wang, X and Chen, L and Qiu, J and Wang, K and Xi, P and Cheng, X and He, Z and Jiang, H},
title = {Dipeptidyl Peptidase 4 Mediated Caspase-8 Affects Cognitive Impairment in Mice With Alzheimer's Disease.},
journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology},
volume = {39},
number = {23},
pages = {e71264},
doi = {10.1096/fj.202501322RR},
pmid = {41307478},
issn = {1530-6860},
support = {82204837//MOST | NSFC | National Natural Science Foundation of China-Zhejiang Joint Fund for the Integration of Industrialization and Informatization (NSFC-Zhejiang Joint Fund)/ ; 81760207//MOST | NSFC | National Natural Science Foundation of China-Zhejiang Joint Fund for the Integration of Industrialization and Informatization (NSFC-Zhejiang Joint Fund)/ ; LQ23H290004//Zhejiang Provincial Natural Science Foundation of China/ ; 2024AY10021//Jiaxing Science and Technology Plan Project‌/ ; },
mesh = {Animals ; *Alzheimer Disease/metabolism ; Male ; Mice ; *Dipeptidyl Peptidase 4/metabolism/genetics ; Mice, Inbred C57BL ; *Caspase 8/metabolism/genetics ; *Cognitive Dysfunction/metabolism ; Mice, Knockout ; Amyloid beta-Peptides/toxicity ; Disease Models, Animal ; Pyroptosis ; Dipeptidyl-Peptidase IV Inhibitors/pharmacology ; Maze Learning ; Hippocampus/metabolism ; Neurons/metabolism ; },
abstract = {To investigate the effect of dipeptidyl peptidase 4 (DPP4) on cognitive impairment in Alzheimer's disease (AD), the present study used seven-week-old male C57BL/6J and DPP4 knockout mice. The AD model was induced by microinjection of Aβ25-35 into the lateral ventricle. Morris water maze test showed that DPP4 knockout significantly improved the spatial learning and memory abilities of AD mice. Western blot results showed that DPP4 knockout increased the expression levels of BDNF, CREB and Bcl-2 in the hippocampus of AD mice while the expression levels of Caspase-8, pyroptosis-related proteins NLRP3, Caspase-1, GSDMD, IL-118, IL-1β, and apoptosis-related proteins Caspase-3 and Bax were decreased. Similar results were observed after HT22 neurons were treated with Aβ25-35 and the DPP4 inhibitor sitagliptin (Sit). Moreover, the treatment with a Caspase-8 inhibitor (Z-LETD-FMK) showed that the inhibition of Caspase-8 inhibited the expression of NLRP3 and Caspase-1 in the AD model cells, but had no further inhibitory effect under the treatment of Sit. Our results suggest that DPP4 knockout may ameliorate learning and memory dysfunction in AD model mice by regulating pyroptosis and apoptosis pathways through Caspase-8.},
}

Animals
*Alzheimer Disease/metabolism
Male
Mice
*Dipeptidyl Peptidase 4/metabolism/genetics
Mice, Inbred C57BL
*Caspase 8/metabolism/genetics
*Cognitive Dysfunction/metabolism
Mice, Knockout
Amyloid beta-Peptides/toxicity
Disease Models, Animal
Pyroptosis
Dipeptidyl-Peptidase IV Inhibitors/pharmacology
Maze Learning
Hippocampus/metabolism
Neurons/metabolism

@article {pmid41307069,
year = {2025},
author = {Zhang, Y and Qiu, J and Shang, Y and Zhao, X and Yang, S and Chen, Y and Dai, S and Ai, M and Huang, W and Zhang, J and Liu, X},
title = {Impact of DL-3-n-Butylphthalide on Progression in Alzheimer's Disease: A Retrospective Cohort Analysis.},
journal = {Neuropsychiatric disease and treatment},
volume = {21},
number = {},
pages = {2495-2511},
pmid = {41307069},
issn = {1176-6328},
abstract = {OBJECTIVE: To evaluate the efficacy of DL-3-n-butylphthalide (NBP), a synthetic compound that has shown neuroprotective effects, on cognitive function, psychiatric-behavioral symptoms, and daily activities in patients with Alzheimer's disease (AD).

METHODS: This retrospective cohort study included patients with AD treated with or without NBP. Disease deterioration and decline were defined by changes in Clinical Dementia Rating-Sum of Boxes (CDR-SB) over six months. Multivariate logistic regression, inverse probability of treatment weighting (IPTW) and overlap-weighted propensity score matching (PSM) were used to adjust for confounding.

RESULTS: Totally 100 were included in this study, with 39 classified as the NBP group and 61 as the non-NBP group. NBP was associated with lower odds of deterioration (adjusted odds ratio [OR] = 0.19, 95% confidence interval [CI]: 0.04-0.88, p = 0.034) and decline (adjusted OR = 0.10, 95% CI: 0.03-0.49, p = 0.001). In IPTW and PSM analyses, deterioration occurred in 4.31% vs 22.10% and 4.06% vs 24.27%, and decline in 4.31% vs 39.38% and 4.06% vs 44.28% for the NBP and non-NBP groups, respectively.

CONCLUSION: NBP was associated with reduced risks of clinical worsening and helped preserve cognitive and behavioral functions in patients with AD. These results highlight the potential of NBP as a promising therapeutic option in AD management. Future randomized controlled trials are necessary to validate these findings and assess the long-term efficacy of NBP in clinical settings.

SIGNIFICANCE: This real-world study suggests that NBP may slow disease progression and preserve cognitive and behavioral function in AD.},
}

@article {pmid41306895,
year = {2025},
author = {Duncan, GB and Dickson, SP and Kaplan, JM and Johnson, SB and Duke, TM and Dayley, CW and Hendrix, SB and Altstiel, LD and Mallinckrodt, CH},
title = {Leveraging recent advances in plasma biomarkers to optimize early proof of concept trials in Alzheimer's disease.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {11},
number = {4},
pages = {e70183},
pmid = {41306895},
issn = {2352-8737},
abstract = {INTRODUCTION: The importance of biomarkers as a primary outcome or as supportive evidence of clinical effect is rising as the field shifts toward disease-modifying treatments and earlier intervention, because they have lower variability and can indicate disease progression earlier than clinical outcomes. This study assessed the performance of plasma pTau 181 and 217 as a predictive biomarker and potential primary endpoint in early-phase Alzheimer's disease (AD) trials.

METHODS: Summary data from recent monoclonal antibody (mAb) trials including plasma pTau 181 and 217 were analyzed to evaluate associations between plasma pTau 181/217 and clinical outcomes. The suitability of plasma pTau 181/217 as a surrogate endpoint for internal decision making was assessed using Prentice criteria. Simulations were conducted to explore the statistical power of using plasma pTau 181/217 as a primary outcome in dose-escalation, proof-of-concept (POC) trial designs. Additional criteria for biomarker validation were applied to simulated data.

RESULTS: A strong group-level correlation (r = 0.781) was observed between treatment effects on plasma pTau 181/217 and Clinical Dementia Rating scale - Sum of Boxes (CDR-SB). Mean change in plasma pTau 181/217 significantly predicted mean change in CDR-SB (p = 0.013). The treatment effect on pTau 181/217 was ∼2.6 times greater than on CDR-SB. Prentice Criteria 1, 2, and 4 were met or reasonably met; Criterion 3 is not applicable in the POC setting.

CONCLUSION: Plasma pTau 181/217 at 6 months shows future promise to reasonably likely predict clinical benefit for drugs that reduce pTau 181/217 levels, supporting its use as a primary endpoint in early-phase trials. With effect sizes similar to those seen with donanemab, adequately powered trials may require as few as 100 participants. Such trials should include prespecified analyses to evaluate individual-level Prentice criteria, and pTau 181/217 results can be used to predict potential Phase 3 clinical outcomes.

HIGHLIGHTS: The group-level correlation between a biomarker treatment effect and clinical endpoint treatment effect is a measurement of the biomarker's ability to predict clinical outcome.The correlation of group level plasma pT217 or pT181 effect size at 6 months with clinical outcome Clinical Dementia Rating scale - Sum of Boxes (CDR-SB) effect size at 12 months was approximately 0.781 with p values of 0.013.Cohen's d effect size of plasma pTau as an outcome was 2.6 times greater than the Cohen's d of CDR-SB, leading to higher power or lower sample sizes.As a primary endpoint, plasma pTau meets or reasonably meets Prentice Criteria 1, 2, and 4, while Criterion 3 was deemed not applicable in the proof-of-concept study setting.},
}

@article {pmid41306402,
year = {2025},
author = {Riberas-Sánchez, A and García-Brito, S and Vila-Solés, L and Aldavert-Vera, L and Segura-Torres, P and Huguet, G and Carreras-Badosa, G and Kádár, E},
title = {Intracranial self-stimulation mitigates spatial task deficits, modifies miR-146a and miR-495 serum levels and restores hippocampal NRF2 levels in a rat model of sporadic Alzheimer's disease.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1671196},
pmid = {41306402},
issn = {1663-4365},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is the most prevalent neurodegenerative disease associated with aging. While deep brain stimulation (DBS) shows therapeutic promise, the long-term persistence of its effects remains understudied. Expression patterns of circulating miRNAs, proposed diagnostic biomarkers, and their modulation by DBS are still poorly characterized in longitudinal studies. This study investigates the effect of a 13-week prolonged ICSS treatment on spatial memory and serum miRNA expression in a male rat model of sporadic AD (SAD) by intracerebroventricular injection of streptozotocin (STZ).

METHODS: Morris water maze (MWM) tasks were conducted at 1 and 5 months post-STZ. Serum miRNA levels were quantified by qRT-PCR at 29 (Ser0), 73 (Ser1) and 136 (Ser2) days after STZ administration. Corpus callosum thickness and NRF2 protein levels in the hippocampal CA1 region were assessed using Nissl staining and immunohistochemistry, respectively. Target validation of miR-495 was performed via transfection assays in the human neuroblastoma SH-SY5Y cell line.

RESULTS: MFB-ICSS treatment significantly reduced escape latency in the MWM task in the STZ + ICSS group compared to untreated STZ rats at 5 months post-STZ. At Ser0, levels of miR-16, miR-30c, miR-181, miR-191 and miR-196a were significantly increased in STZ group. In STZ rats, miR-146a and miR-495 levels increased from Ser1 to Ser2, an effect not observed in the Control or STZ + ICSS groups. In SH-SY5Y cells, miR-495 overexpression significantly downregulated both NRF2 mRNA and protein levels. Moreover, STZ exposure increased miR-495 and reduced NRF2 protein levels. MFB-ICSS also reversed the STZ-induced reductions in both CA1 NRF2 levels and corpus callosum thickness.

CONCLUSION: Prolonged MFB-ICSS treatment mitigates cognitive deficits, modulates circulating levels of miRNA-495 and miR-146a, restores hippocampal NRF2 levels, and preserves corpus callosum integrity in the SAD rat model by STZ injection. These findings highlight the therapeutic potential of MFB-ICSS as a non-pharmacological intervention in AD. Furthermore, this study confirms NRF2 as a target of miR-495 in the context of AD.},
}

@article {pmid41306115,
year = {2025},
author = {Li, G and Cobb, B and Nelson, TM and Devanarayan, V and Borentain, S and Mielke, MM and Galvin, JE and Kivipelto, M and Tkatch, R and De Santi, S and Frech, F and Vandercappellen, J and Nakamura, Y and Crislip, R and Meyerhoff, J and Mattke, S and Hampel, H},
title = {Risk prediction of mild cognitive impairment using electronic health record data.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {17},
number = {4},
pages = {e70209},
pmid = {41306115},
issn = {2352-8729},
abstract = {INTRODUCTION: Mild cognitive impairment (MCI) is underdiagnosed by primary care providers (PCPs), with detection rates as low as 6%-15%. Predictive models support the identification of individuals at risk, enabling timely intervention.

METHODS: This retrospective study was conducted on 271,054 cognitively unimpaired and 14,501 confirmed MCI cohorts from electronic health records. A machine learning model was developed with a data-driven variable selection approach based on demographics and comorbidities.

RESULTS: From 101 variables, 26 were chosen for the final model, achieving an overall area under the curve (AUC) of 86%. Age-stratified AUCs were 79.1% (40-49), 77.0% (50-64), 76.9% (65-79), and 74.4% (≥80), showing the highest predictive performance in younger age groups.

DISCUSSION: Demographic factors and comorbidities can serve as effective predictors for the risk of MCI. The model demonstrates strong predictive performance and assists as a triage tool for PCPs, facilitating the identification of individuals with MCI for early treatment.

HIGHLIGHTS: Predictive algorithms using electronic health records (EHRs) are useful for identifying individuals at risk for mild cognitive impairment (MCI) to triage for further clinical evaluation.A machine learning model was developed using EHR data to predict those at risk for MCI.The model identified 26 variables that were able to distinguish the MCI from non-MCI cohorts.The model accurately detected MCI across the cohort (area under the curve [AUC] = 86%) and trended best for younger age groups (AUC was 77%, 77%, and 74% in 50-64, 65-79, and ≥80 age groups, respectively).Implementation of a triage tool could be used to detect MCI across aging patient populations sooner, leading to a timelier diagnosis, intervention, and treatment management.},
}

@article {pmid41304967,
year = {2025},
author = {Akantibila, M and Carabetta, VJ},
title = {Sirtuins as Therapeutic Targets for Treating Cancer, Metabolic Diseases, and Neurodegenerative Diseases.},
journal = {Pharmaceuticals (Basel, Switzerland)},
volume = {18},
number = {11},
pages = {},
doi = {10.3390/ph18111723},
pmid = {41304967},
issn = {1424-8247},
support = {R35GM138303/GM/NIGMS NIH HHS/United States ; },
abstract = {Sirtuins are NAD[+]-dependent enzymes that are conserved in all domains of life, including mammals, metazoans, plasmodia, yeast, bacteria, and archaea. In humans, there are seven isoforms (SIRT1 to 7), and they function in cellular homeostasis, aging, DNA repair, survival, metabolism, and stress responses. Recent advances highlight the diverse functions of sirtuins in the pathogenesis and progression of cancer, metabolic diseases, and neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD). To date, there is evidence that all seven isoforms contribute to cancer development, while SIRT1-3 and 6 contribute to metabolic and neurodegenerative diseases. Modulators of sirtuin activity are being actively explored to understand their biological and molecular mechanisms and potential for the treatment of various diseases. In this review, we begin with a broad discussion of post-translational modifications, protein deacetylation, and the mechanism of action of sirtuins. Next, we discuss the role of sirtuins in cancer, including inhibitors and activators of sirtuin activity as cancer therapies. In addition, we discuss the relationship of sirtuins to metabolic diseases and as possible treatment targets. Finally, we discuss the role of sirtuins in AD, PD, and HD, and sirtuin modulators for treating neurodegenerative diseases.},
}

@article {pmid41304930,
year = {2025},
author = {Almaghrabi, M},
title = {Multitarget-Directed Ligands for Alzheimer's Disease: Recent Novel MTDLs and Mechanistic Insights.},
journal = {Pharmaceuticals (Basel, Switzerland)},
volume = {18},
number = {11},
pages = {},
doi = {10.3390/ph18111685},
pmid = {41304930},
issn = {1424-8247},
support = {447-13-1011//Taibah University/ ; },
abstract = {Alzheimer's disease (AD) is the most prevalent neurodegenerative disease, affecting millions of people and challenging the public health framework globally. While the definitive cause of AD remains unclear, researchers are concentrating their efforts on several prominent theories. Currently, there are very few FDA-approved medications for AD, and these primarily alleviate symptoms rather than alter the disease's progression. In response, research efforts focus on developing new medicines that address the complex nature of AD through multi-targeted approaches. Multitarget-directed ligands (MTDLs) are a promising treatment strategy for AD, despite the significant challenges they pose. This review examines recent advancements in designing prospective targeted MTDLs to combat AD, with a focus on categorizing the lead generation process and investigating the integration methods of key pharmacophores within the 2024-2025 timeframe. The review highlights numerous examples of novel MTDLs that address various AD hallmarks, demonstrating their broad therapeutic potential. These targets and activities include cholinesterase (AChE and/or BuChE) inhibition, monoamine oxidase (MAO-A and/or MAO-B) inhibition, antioxidant activity, amyloid-beta (Aβ) aggregation inhibition, tau protein aggregation inhibition, glycogen synthase kinase 3β (GSK-3β) inhibition, calcium channel blockade, anti-inflammatory activity, and other hallmarks.},
}

@article {pmid41304419,
year = {2025},
author = {Ezzaki, C and Chaari, A and Al-Othman, A},
title = {Recent Advances on Chitosan-Based Nanoparticles for Brain Drug Delivery.},
journal = {Polymers},
volume = {17},
number = {22},
pages = {},
doi = {10.3390/polym17223055},
pmid = {41304419},
issn = {2073-4360},
abstract = {The blood-brain barrier (BBB) represents a major challenge in effective drug delivery systems intended for treating neurological disorders. It restricts the transport of therapeutic agents to the brain. Chitosan-based nanoparticles (CNPs) can be used for brain drug delivery because of their biocompatibility, biodegradability, and ability to enhance drug permeability across the BBB. This review article discusses the design and application of CNPs for brain-targeted drug delivery, exploring their mechanisms of action, including adsorptive-mediated and receptor-mediated endocytosis. Surface modifications with ligands such as chlorotoxin are discussed for improving specificity and therapeutic results. Findings show that CNPs allow controlled drug release, enhance stability, and reduce side effects, which make them effective for treating multiple neurological conditions, including Alzheimer's disease, Parkinson's disease, brain tumors, and ischemic stroke. CNPs can encapsulate multiple therapeutic agents, such as anti-inflammatory drugs, cytotoxic agents, and genetic materials, and maintain stability under different physiological conditions. Intranasal delivery routes are mainly discussed in this paper for their ability to bypass systemic circulation and achieve direct brain targeting. This review also addresses challenges such as cytotoxicity and the need for optimizing nanoparticle size, charge, and surface properties to improve the therapy results. While CNPs are suitable for brain drug delivery, there is a research gap, which is the lack of systematic studies evaluating their long-term effects on brain tissue and health. Most studies focus on acute therapeutic outcomes and in vitro or short-term in vivo analysis, which do not address some questions about the chronic exposure risks, biodistribution, and clearance pathways of CNPs. This review also explores the use of chitosan-based nanoparticles to deliver drugs to the brain for the treatment of multiple neurological disorders.},
}

@article {pmid41303831,
year = {2025},
author = {Uehara, MA and Kalia, S and Garcia Campuzano, M and Moussavi, Z},
title = {ADAS-Cog Trajectories Differ from Expected Decline in Dementia Following Repeated Non-Invasive Interventions over 3 Years.},
journal = {Medicina (Kaunas, Lithuania)},
volume = {61},
number = {11},
pages = {},
doi = {10.3390/medicina61111994},
pmid = {41303831},
issn = {1648-9144},
support = {RGPIN-2023-04308//Natural Sciences and Engineering Research Council of Canada/ ; IT43832//Mitacs/ ; },
mesh = {Humans ; Male ; Female ; Aged ; *Dementia/therapy/psychology ; Aged, 80 and over ; Transcranial Magnetic Stimulation/methods ; *Cognitive Dysfunction/therapy ; Disease Progression ; Alzheimer Disease/therapy/psychology ; Longitudinal Studies ; Neuropsychological Tests ; Middle Aged ; Mental Status and Dementia Tests ; },
abstract = {Background and Objectives: Non-pharmaceutical interventions such as cognitive training, transcranial electrical stimulation (tES), and repetitive transcranial magnetic stimulation (rTMS) have shown promise in improving cognitive outcomes in Alzheimer's disease (AD) and dementia. However, the long-term effects of repeated non-invasive interventions remain unknown. This study investigated whether repeated non-invasive interventions administered over a span of 1 to 3 years were associated with slower cognitive decline compared to typical AD progression, and whether longer no-treatment intervals between treatments predicted greater post-treatment decline. Materials and Methods: Seventy-three participants living with dementia or AD received 2 to 9 blocks of non-invasive treatments (including tES, rTMS, cognitive training). Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog) scores were collected longitudinally up to 3 years (36 months), across multiple intervention and assessment sessions. A mixed-effects model was used to estimate the rate of cognitive decline, adjusting for baseline age, sex, and baseline cognition (MoCA) with participants being the random effect. The observed rate of change was compared to a meta-analysis estimate of AD progression. Additionally, a linear mixed-effects model using robust sandwich estimation of standard errors was employed to assess whether the no-treatment interval was associated with changes in ADAS-Cog scores. Results: Participants showed a significantly slower rate of cognitive decline than expected from the AD reference rate (p < 0.001), with many demonstrating stabilized ADAS-Cog scores during their respective treatment periods, ranging from 1 to 3 years. Medication analyses revealed no significant effect of AD medications, antidepressants, antihypertensives, or cholesterol-lowering agents on cognitive outcomes. Furthermore, longer no-treatment intervals were significantly associated with greater post-treatment decline (p < 0.001). Conclusions: Repeated non-invasive treatments seem to slow the rate of cognitive decline in individuals living with dementia when administered over a prolonged period. This study provides evidence supporting the feasibility and effects of personalized long-term non-invasive treatment strategies for dementia.},
}

Humans
Male
Female
Aged
*Dementia/therapy/psychology
Aged, 80 and over
Transcranial Magnetic Stimulation/methods
*Cognitive Dysfunction/therapy
Disease Progression
Alzheimer Disease/therapy/psychology
Longitudinal Studies
Neuropsychological Tests
Middle Aged
Mental Status and Dementia Tests

@article {pmid41303478,
year = {2025},
author = {Polishchuk, H and Guzik, K and Kantyka, T},
title = {Beyond Hunger: The Structure, Signaling, and Systemic Roles of Ghrelin.},
journal = {International journal of molecular sciences},
volume = {26},
number = {22},
pages = {},
doi = {10.3390/ijms262210996},
pmid = {41303478},
issn = {1422-0067},
support = {UMO-2016/22/E/NZ5/00332//National Science Centre/ ; },
mesh = {*Ghrelin/metabolism/chemistry ; Humans ; *Signal Transduction ; Animals ; *Receptors, Ghrelin/metabolism/chemistry ; *Hunger/physiology ; },
abstract = {Our understanding of Ghrelin, an endogenous ligand of the growth hormone secretagogue receptor 1a (GHSR1a), has expanded from considering it to be a "hunger hormone" to a pleiotropic regulator of whole-body physiology. This review synthesizes the current advances spanning ghrelin biogenesis, signaling, and systems biology. Physiologically, preproghrelin processing and O-acylation by ghrelin O-acyltransferase (GOAT) generate acyl-ghrelin, a high-potency GHSR1a agonist; des-acyl ghrelin predominates in circulation and exerts context-dependent, GHSR1a-independent, or low-potency effects, while truncated "mini-ghrelins" can act as competitive antagonists. The emergence of synthetic ligands, agonists, antagonists, and reverse-agonists has provided the necessary tools to decipher GHSR1a activity. Recent cryo-EM structures of GHSR1a with peptide and small-molecule ligands reveal a bipartite binding pocket and provide a framework for biased signaling, constitutive activity, and receptor partner selectivity. Beyond the regulation of feeding and growth-hormone release, ghrelin modulates glucose homeostasis, gastric secretion and motility, cardiovascular tone, bone remodeling, renal hemodynamics, and innate immunity. Ghrelin broadly dampens pro-inflammatory responses and promotes reparative macrophage phenotypes. In the emerging scholarship on ghrelin's activity in the central nervous system, ghrelin has been found to influence neuroprotection, stress reactivity, and sleep architecture, and has also been implicated in depression, Alzheimer's disease, and substance-abuse disorders. Practical and transitional aspects are also highlighted in the literature: approaches for ghrelin stabilization; recent GHSR1a agonists/antagonists and inverse agonists findings; LEAP-2-based strategies; and emerging GOAT inhibitors. Together, structural insights and pathway selectivity position the ghrelin system as a druggable axis for the management of inflammatory diseases, neuropsychiatric and addiction conditions, and for obesity treatment in the post-GLP-1 receptor agonist era.},
}

*Ghrelin/metabolism/chemistry
Humans
*Signal Transduction
Animals
*Receptors, Ghrelin/metabolism/chemistry
*Hunger/physiology

@article {pmid41303365,
year = {2025},
author = {Faa, G and Meloni, C and Lastretti, M and Pinna, M and Manchia, M and Paribello, P},
title = {Perturbations of Zinc Homeostasis and Onset of Neuropsychiatric Disorders.},
journal = {International journal of molecular sciences},
volume = {26},
number = {22},
pages = {},
doi = {10.3390/ijms262210877},
pmid = {41303365},
issn = {1422-0067},
mesh = {Humans ; *Zinc/metabolism ; *Homeostasis ; *Mental Disorders/metabolism/etiology ; Attention Deficit Disorder with Hyperactivity/metabolism ; Animals ; Schizophrenia/metabolism ; Depressive Disorder, Major/metabolism ; Alzheimer Disease/metabolism ; Autism Spectrum Disorder/metabolism ; Parkinson Disease/metabolism ; Bipolar Disorder/metabolism ; },
abstract = {Zinc (Zn[2+]) is a trace element essential for its catalytic, antioxidant, and immunomodulatory roles extending to synaptic signalling in the central nervous system. In this narrative review, we aim to offer the reader evidence linking perturbations of the Zn[2+] homeostasis, including deficiency, excess, or transportation anomalies, to neuropsychiatric conditions such as Alzheimer's disease (AD), Parkinson's disease (PD), autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), schizophrenia (SCZ), major depressive disorder (MDD), and bipolar disorder (BD). A targeted, unsystematic PubMed search followed by an extensive pearl-growing strategy was applied to further augment study selection based on the extensive expertise of study authors. Overall, most of the evidence currently available suggests a modest benefit for a Zn[2+] supplement of around 25-30 mg/day as an augmentation to MDD treatment, with potential benefits of smaller magnitude in paediatric ADHD. Evidence for perturbations of Zn[2+] as a biomarker of risk for these neuropsychiatric disorders remains unconvincing. The role of Zn[2+] supplements in the treatment of the selected conditions remains largely unknown due to the lack of specific, randomised controlled trials conducted to explore their efficacy. The long-term safety, optimal doses for specific applications, and the exploration of possible biomarkers to stratify patient selection to identify the optimal candidate for Zn[2+] supplements remain unanswered questions.},
}

Humans
*Zinc/metabolism
*Homeostasis
*Mental Disorders/metabolism/etiology
Attention Deficit Disorder with Hyperactivity/metabolism
Animals
Schizophrenia/metabolism
Depressive Disorder, Major/metabolism
Alzheimer Disease/metabolism
Autism Spectrum Disorder/metabolism
Parkinson Disease/metabolism
Bipolar Disorder/metabolism

@article {pmid41303334,
year = {2025},
author = {Pecoraro, M and Serra, A and Lamberti, MJ and Pascale, M and Franceschelli, S},
title = {New Role of Protein Misfolding Corrector in the ER Stress-Inflammation Axis: Possible Therapeutic Indication in Neuronal and Epithelial Tumor Cells.},
journal = {International journal of molecular sciences},
volume = {26},
number = {22},
pages = {},
doi = {10.3390/ijms262210846},
pmid = {41303334},
issn = {1422-0067},
support = {ORSA231580//University of Salerno/ ; },
mesh = {Humans ; *Endoplasmic Reticulum Stress/drug effects ; *Inflammation/metabolism/drug therapy ; *Neurons/metabolism/drug effects/pathology ; Protein Folding/drug effects ; Calcium/metabolism ; Cell Line, Tumor ; Thapsigargin/pharmacology ; A549 Cells ; Epithelial Cells/metabolism/drug effects ; Proteostasis Deficiencies/drug therapy/metabolism ; },
abstract = {Protein misfolding diseases are characterized by structurally abnormal proteins that lose their functionality, resulting in cellular and tissue dysfunction. Neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease and Huntington's disease, share a common etiopathogenesis characterize by the accumulation of misfolded proteins. These proteins autonomously aggregate within neuronal cells, triggering inflammation and cell death. The accumulation of misfolded proteins triggers endoplasmic reticulum (ER) stress, leading to alter Ca[2+] homeostasis. This prolonged stress condition induces the cleavage of procaspase 4 which is resident in ER and activates NF-kB pathway activation, leading to inflammatory responses and cell death. In this study, the efficacy of the drug Vx-445 (Elexacaftor), used in the pharmacological treatment of cystic fibrosis, was assessed in human adenocarcinomic basal alveolar epithelial (A549) and neuronal (SH-SY5Y) cell lines, where ER stress was induced by Thapsigargin. The aim was to assess whether the corrector was able to reduce ER stress by restoring cellular homeostasis and, probably, the proper folding of misfolded proteins and reducing the inflammatory response triggered by these events. Therefore, protein levels of IkBα, p-STAT 3 and COXII were analyzed by flow cytofluorimetry, while Ca[2+] content was measured by spectrofluorimetry. The results obtained suggest a significant effect of Vx-445 in restoring cellular homeostasis, leading to reduced expression of inflammation-related proteins, such as IL-6, tested by ELISA. Although preliminary, these results encourage further studies to explore the potential repurpose of Vx-445 as a therapeutic candidate for conditions involving ER stress and chronic inflammatory diseases associated with protein misfolding, beyond its current use in cystic fibrosis.},
}

Humans
*Endoplasmic Reticulum Stress/drug effects
*Inflammation/metabolism/drug therapy
*Neurons/metabolism/drug effects/pathology
Protein Folding/drug effects
Calcium/metabolism
Cell Line, Tumor
Thapsigargin/pharmacology
A549 Cells
Epithelial Cells/metabolism/drug effects
Proteostasis Deficiencies/drug therapy/metabolism

@article {pmid41301832,
year = {2025},
author = {Christodoulou, RC and Papageorgiou, PS and Sarquis, MD and Rivera, L and Morales Gonzalez, C and Eller, D and Rivera, G and Petrou, V and Vamvouras, G and Vassiliou, E and Papageorgiou, SG and Georgiou, MF},
title = {From Lesion to Decision: AI for ARIA Detection and Predictive Imaging in Alzheimer's Disease.},
journal = {Biomedicines},
volume = {13},
number = {11},
pages = {},
doi = {10.3390/biomedicines13112739},
pmid = {41301832},
issn = {2227-9059},
abstract = {Background: Alzheimer's disease (AD) remains the leading cause of dementia worldwide, with anti-amyloid monoclonal antibodies (MABs) marking a significant advance as the first disease-modifying therapies. Their use, however, is limited by amyloid-related imaging abnormalities (ARIA), which appear as vasogenic edema or effusion (ARIA-E) and hemosiderin-related changes (ARIA-H) on MRI. Variability in imaging protocols, subtle early findings, and the lack of standardized risk models challenge detection and management. Methods: This narrative review summarizes current artificial intelligence (AI) applications for ARIA detection and risk prediction. A comprehensive literature search across PubMed, Embase, and Scopus identified studies focusing on MRI-based AI analysis, lesion quantification, and predictive modeling. Results: The evidence is organized into six thematic domains: ARIA definitions, imaging challenges, foundations of AI in neuroimaging, detection tools, predictive frameworks, and future perspectives. Conclusions: AI offers promising avenues to standardize ARIA evaluation, improve lesion quantification, and enable individualized risk prediction. Progress will depend on multicenter datasets, shared frameworks, and prospective validation. Ultimately, AI-driven neuroimaging may transform how treatment-related complications are monitored in the era of anti-amyloid therapy.},
}

@article {pmid41301782,
year = {2025},
author = {Christodoulou, RC and Vamvouras, G and Papageorgiou, PS and Sarquis, MD and Petrou, V and Rivera, L and Morales, C and Rivera, G and Papageorgiou, SG and Vassiliou, E},
title = {Interpretable Machine Learning for Risk Stratification of Hippocampal Atrophy in Alzheimer's Disease Using CSF Erythrocyte Load and Clinical Data.},
journal = {Biomedicines},
volume = {13},
number = {11},
pages = {},
doi = {10.3390/biomedicines13112689},
pmid = {41301782},
issn = {2227-9059},
abstract = {Background/Objectives: Hippocampal atrophy indicates Alzheimer's disease (AD) progression and guides follow-up and trial enrichment. Identifying high-risk patients is crucial for optimizing care, but accessible, interpretable machine-learning models (ML) are limited. We developed an explainable ML model using clinical data and CSF erythrocyte load (CTRED) to classify adults with AD as high- or low-risk based on hippocampal volume decline. Methods: Included ADNI participants with ≥2 MRIs, baseline lumbar puncture, and vital signs within 6 months of MRI (n = 26). The outcome was the Annual Percentage Change (APC) in hippocampal volume, classified as low or high risk. Predictors were standardized; models included SVM, logistic regression, and Ridge Classifier, tuned and tested on a set (n = 6). Thresholds were based on out-of-fold predictions under a 10-90% positive rate. Explainability used PFI and SHAP for per-patient contributions. Results: All models gave identical classifications, but discrimination varied: Ridge AUC = 1.00, logistic = 0.889, and SVM = 0.667. PFI highlighted MAPres and sex as main signals; CTRED contributed, and age had a minor impact. Conclusions: The explainable ML model with clinical data and CTRED can stratify AD patients by hippocampal atrophy risk, aiding follow-up and vascular assessment planning rather than treatment decisions. Validation in larger cohorts is needed. This is the first ML study to use CSF erythrocyte load to predict hippocampal atrophy risk in AD.},
}

@article {pmid41301520,
year = {2025},
author = {Lope-Piedrafita, S and Serra-Mir, G and Melón, P and Bonaterra, A and Hernández-Guillamon, M and Villegas, S},
title = {ScFv-h3D6 Prevents Bapineuzumab-Induced Hemorrhagic Events in the APP23 Mouse Model of Alzheimer's Disease.},
journal = {Biomolecules},
volume = {15},
number = {11},
pages = {},
doi = {10.3390/biom15111602},
pmid = {41301520},
issn = {2218-273X},
support = {SAF2017-89613R//Ministerio de Economía y Empresa, Spain/ ; PI17-00275//Instituto de Salud Carlos III/ ; },
mesh = {Animals ; *Alzheimer Disease/drug therapy/pathology/metabolism/genetics/diagnostic imaging ; *Single-Chain Antibodies/pharmacology ; Mice ; Disease Models, Animal ; Mice, Transgenic ; *Antibodies, Monoclonal, Humanized/adverse effects ; Humans ; Amyloid beta-Peptides/metabolism ; Cerebral Amyloid Angiopathy/drug therapy ; Magnetic Resonance Imaging ; Amyloid beta-Protein Precursor/genetics ; },
abstract = {The occurrence of amyloid-related imaging abnormalities (ARIAs), found in clinical trials for Aβ-immunotherapy, has been related to the antibody's effector function on glial activation by the Fc portion of the antibody. The use of single-chain variable fragments (scFv) has been proposed as a safer therapeutic strategy. Here, the effects of the mice format of bapineuzumap (mAb-m3D6) and its scFv (scFv-h3D6) on the occurrence of ARIAs in the APP23 mouse model of Alzheimer's disease (AD) and cerebral amyloid angiopathy (CAA) have been addressed by magnetic resonance imaging (MRI). Results are supported by histological and/or biochemical determinations. Aged APP23 mice showed a significantly higher number of microhemorrhages than non-transgenic mice. mAb-m3D6 produced an increase in the number of new hemorrhagic events, mainly in the cortex, whereas scFv-h3D6 did not. Both mAb-m3D6 and scFv-h3D6 reduced Aβ levels by the same extent. Axonal/myelin damage was found in the frontal corpus callosum of APP23 mice, which did not recover after treatment. In conclusion, the scFv-h3D6 format appears safer than the full-length mAb in the APP23 model of AD and CAA. This finding is highly relevant in light of the new FDA- and EMA-approved mAbs, which exclude APOEε4 allele carriers due to the occurrence of hemorrhages.},
}

Animals
*Alzheimer Disease/drug therapy/pathology/metabolism/genetics/diagnostic imaging
*Single-Chain Antibodies/pharmacology
Mice
Disease Models, Animal
Mice, Transgenic
*Antibodies, Monoclonal, Humanized/adverse effects
Humans
Amyloid beta-Peptides/metabolism
Cerebral Amyloid Angiopathy/drug therapy
Magnetic Resonance Imaging
Amyloid beta-Protein Precursor/genetics

@article {pmid41301403,
year = {2025},
author = {Zhang, S and Liu, X and Xu, S and Li, W and Song, J and Tian, Q and Du, Y},
title = {Multi-Omics Integration Reveals Electroacupuncture Ameliorates Cognitive Impairment in Alzheimer's Disease via Gut-Brain Axis.},
journal = {Biomolecules},
volume = {15},
number = {11},
pages = {},
doi = {10.3390/biom15111486},
pmid = {41301403},
issn = {2218-273X},
support = {82374564//National Natural Science Foundation of China/ ; 81873380//National Natural Science Foundation of China/ ; 82074566//National Natural Science Foundation of China/ ; 2025AFD596//Hubei Provincial Joint Fund Project/ ; },
mesh = {Animals ; *Electroacupuncture/methods ; *Alzheimer Disease/therapy/metabolism/microbiology ; Mice ; *Gastrointestinal Microbiome ; *Cognitive Dysfunction/therapy/metabolism ; Male ; *Brain/metabolism ; Disease Models, Animal ; Metabolomics ; RNA, Ribosomal, 16S/genetics ; Metabolome ; *Brain-Gut Axis ; Multiomics ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) lacks effective therapeutic strategies. Electroacupuncture (EA) offers promising neuroprotective effects, but its underlying mechanisms remain unclear.

OBJECTIVE: To explore the mechanisms of EA's neuroprotective effects on AD via microbiome and metabolome integration.

METHODS: Utilizing a well-established model of AD, Senescence-Accelerated Mouse Prone 8 (SAMP8), EA intervention was performed. 16S ribosomal RNA (rRNA) sequencing and serum metabolomics were conducted on SAMP8 mice, SAMP8 mice after EA intervention, and their normal control group Senescence-Accelerated Mouse Resistant 1 (SAMR1) mice.

RESULTS: SAMP8 mice were subjected to electroacupuncture (EA) treatment at the Baihui (GV20) and Shenshu (BL23) acupoints for 15 min daily over a period of four weeks. EA enhanced cognitive function and reduced neuronal damage in AD models. The treatment lowered pro-inflammatory cytokines (TNF-α, IL-1β) and AD-related pathologies (tau, Aβ1-42). EA also rebalanced gut microbiota by increasing beneficial Gastranaerophilales while decreasing harmful Proteobacteria. Additionally, it restored purine and phenylpropanoid metabolism by regulating key metabolites. Importantly, EA reduced levels of specific metabolites linked to pro-inflammatory bacteria (Sphingomonas, Massilia, Escherichia-Shigella), simultaneously decreasing their abundance. These findings highlight EA's multi-target effects on neuroinflammation, gut microbiota, and metabolic pathways in AD. Notably, the interactions between EA-regulated key metabolites and AD-related targets, predicted via PubChem and ChEMBL databases, remain computational and have not been validated by experimental studies.

CONCLUSIONS: EA exerts neuroprotective effects in AD via modulation of gut microbiota and metabolic pathways, representing a novel non-pharmacological therapeutic strategy.},
}

Animals
*Electroacupuncture/methods
*Alzheimer Disease/therapy/metabolism/microbiology
Mice
*Gastrointestinal Microbiome
*Cognitive Dysfunction/therapy/metabolism
Male
*Brain/metabolism
Disease Models, Animal
Metabolomics
RNA, Ribosomal, 16S/genetics
Metabolome
*Brain-Gut Axis
Multiomics

@article {pmid41301354,
year = {2025},
author = {Gao, J and Liu, L and Yang, Z and Fan, J and For The Alzheimer's Disease Neuroimaging Initiative, },
title = {Predictors of Transition from Mild Cognitive Impairment to Normal Cognition and Dementia.},
journal = {Behavioral sciences (Basel, Switzerland)},
volume = {15},
number = {11},
pages = {},
doi = {10.3390/bs15111552},
pmid = {41301354},
issn = {2076-328X},
support = {2024-BS-160//Natural Science Foundation of Liaoning Province/ ; LJ212410165004//Education Department Project of Liaoning Province/ ; 2024BSL004//Ph.D. Start-up Project of Liaoning Normal University/ ; },
abstract = {Mild cognitive impairment (MCI) represents a heterogeneous state between normal aging and dementia, with varied transition pathways. While factors influencing MCI progression are known, their role in cognitive reversal is unclear. This study analyzed 756 Alzheimer's Disease Neuroimaging Initiative (ADNI) participants, classified as progressive MCI (pMCI, N = 272, mean age = 75.10 ± 7.34 years), reversible MCI (rMCI, N = 52, mean age = 69.94 ± 7.98 years) and stable MCI (sMCI, N = 432, mean age = 73.34 ± 7.44 years) based on 36-month follow-up. We compared demographic, lifestyle, clinical, cognitive, neuroimaging, and biomarker data across groups and developed a prediction model. Patients in the rMCI group were significantly younger and had a higher level of education compared with those in the pMCI group. Memory, general cognition, daily functional activities, and hippocampal volume effectively distinguished all three groups. In contrast, Aβ, tau, and other brain regions were able to distinguish only between progressive and non-progressive cases. Informant-reported Everyday Cognition (Ecog) scales outperformed self-reported Ecog scales in differentiating subtypes and predicting progression. Multinomial regression revealed that higher education, larger hippocampal volume, and lower daily functional impairment were associated with reversion, whereas APOE ε4, poorer memory, and greater brain atrophy predicted progression (model accuracy: 78%). The results confirm the significant utility of hippocampal volume, education level, and daily functional activities for assessing baseline disparities and predicting reversion. This study highlights the differential contributions of cognitive abilities and brain regions on MCI reversal, advancing understanding of MCI heterogeneity and providing evidence for precise diagnosis and treatment in early MCI.},
}

@article {pmid41300531,
year = {2025},
author = {Valle, ML and Getaneh, B and William, C and Ghiso, J and Rostagno, A},
title = {Antioxidants Trolox and Methazolamide Protect Microvascular Endothelial Cells from Oxidative Damage Induced by Sporadic and Familial Forms of Oligomeric Amyloid-β.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {14},
number = {11},
pages = {},
doi = {10.3390/antiox14111375},
pmid = {41300531},
issn = {2076-3921},
support = {AG065651//National Institute of Health/ ; },
abstract = {Cerebral amyloid angiopathy (CAA), present in more than 90% of Alzheimer's disease (AD) cases, associates with focal ischemia and neurovascular dysfunction. Genetic variants at positions 21-23 of amyloid beta (Aβ), among them the Dutch mutation (AβE22Q), are primarily linked to CAA and the development of cerebral hemorrhages. An important contributor to CAA pathogenesis is the dysregulation of mitochondria-mediated pathways with concomitant induction of oxidative stress. Using biochemical assays and immunofluorescence microscopy, this work demonstrates the exacerbated formation of reactive oxygen species (ROS) in human brain microvascular endothelial cells after short exposure to soluble oligomers of synthetic homologues of Aβ1-42 and the Dutch variant, inducing lipid peroxidation and protein carbonylation, both markers of oxidative stress. The heterogeneity of the soluble oligomeric assemblies inducing this oxidative response was highlighted by their reactivity with two conformational antibodies recognizing specific and mutually exclusive epitopes associated with either soluble prefibrillar oligomers or soluble fibrillar oligomers. Treatment with the multitarget antioxidants Trolox and methazolamide significantly attenuated the Aβ-mediated ROS production and reduced oxidative stress markers to basal levels. Our data highlight the damaging role of heterogeneous Aβ oligomers and the preventing effect of antioxidants, suggesting ROS modulation as a complementary therapeutic strategy to preserve neurovascular unit integrity.},
}

@article {pmid41300478,
year = {2025},
author = {Fu, Y and Zhang, X and Li, L and Jiang, H and Ren, Q and Yi, T and Zhang, Y and Lu, Y},
title = {PPARα-Mediated Fatty Acid Catabolism in Astrocytes Was Involved in Improvement of Cognitive Dysfunction by Phlorizin in APP/PS1 Mice.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {14},
number = {11},
pages = {},
doi = {10.3390/antiox14111321},
pmid = {41300478},
issn = {2076-3921},
support = {7252230//Yi Lu/ ; },
abstract = {Central lipid metabolism disorders are crucial for the development of Alzheimer's disease (AD). Phlorizin (PHZ) improved lipid metabolism abnormalities in AD nematodes, but its mechanism of action in improving AD-related symptoms and whether it can alleviate AD cognitive impairment remain unclear. To elucidate the effects and mechanisms of PHZ on lipid metabolism disorders in an AD model, gavage administration of PHZ for 8 weeks improved cognitive dysfunction and lipid disorders in APPswe/PSEN1dE9 (APP/PS1) mice. Concurrently, in astrocytes induced by palmitic acid (PA)- mediated lipid metabolic disorder, PHZ treatment improved astrocytic lipid accumulation by upregulating the target peroxisome proliferator-activated receptor α (PPARα) and its downstream pathways, thereby promoting astrocytic fatty acid oxidation. We validated PHZ's strong in vitro binding affinity with PPARα. Co-culture systems of lipid-metabolically disordered astrocytes and neurons further demonstrated that PHZ significantly improved neuronal cell viability and reduced intracellular lipid accumulation, thereby decreasing the expression of enzymes associated with β-amyloid protein (Aβ) production. This study demonstrates that gavage administration of PHZ for 2 months improves cognitive deficits and pathological markers in AD mice. Furthermore, at the cellular level, PHZ may exert its effects by enhancing astrocytic lipid metabolism, thereby preventing neuronal lipotoxicity and mitigating AD progression.},
}

@article {pmid41300346,
year = {2025},
author = {Yeasmin, A and Torrente, MP},
title = {Histone Post-Translational Modifications and DNA Double-Strand Break Repair in Neurodegenerative Diseases: An Epigenetic Perspective.},
journal = {Biology},
volume = {14},
number = {11},
pages = {},
doi = {10.3390/biology14111556},
pmid = {41300346},
issn = {2079-7737},
support = {1R15NS125394-01/NH/NIH HHS/United States ; },
abstract = {DNA damage is a hallmark of the fatal process of neurodegeneration in the central nervous system (CNS). As neurons are terminally differentiated, they accumulate metabolic and oxidative burdens over their whole life span. Unrepaired DNA develops into DNA double-strand breaks (DSBs), which are repaired through homologous recombination (HR) or non-homologous end joining (NHEJ). Being post-mitotic and unable to normally undergo HR, damage and defective repair is especially burdensome to CNS neurons. Current research has not produced treatment to prevent and halt progression of neurodegeneration. Hence, novel targeting strategies are desperately needed. Recent investigations in histone post-translational modifications (PTMs) reveal new mechanistic insight and highlight unexplored targets to ameliorate neurodegeneration. As various histone PTMs dictate and facilitate DSB repair, they represent an underexploited area in investigating DNA damage and incorrect repair aiding neurodegeneration. Here, we review the histone PTM alterations in several neurodegenerative diseases: Amyotrophic Lateral Sclerosis/Frontotemporal Dementia, Parkinson's Disease, Alzheimer's Diseases, Multiple Sclerosis, and Huntington's Disease. These findings emphasize that histone PTM alterations can enable an aberrant DNA damage response (DDR) leading to neurodegeneration. Further research into the connections between histone PTMs and DNA damage in decaying neurons will illuminate novel targets to dampen the aberrant DDR and promote neuronal survival.},
}