@article {pmid41315611,
year = {2025},
author = {Wang, G and Liu, S and Liu, G and Fan, N and Zhang, W and Dong, W and Yin, J},
title = {Abnormal glycosylation changes in brain tissue of kainic acid-induced epileptic rats.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-025-29690-z},
pmid = {41315611},
issn = {2045-2322},
support = {2024-BS-179//Doctoral research Foundation of Liaoning Province/ ; 32171280//National Nature Science Foundation of China Research Grant/ ; JCHZ2023013//Dalian Medical University Interdisciplinary Research Cooperation Project Team/ ; },
abstract = {Epilepsy is a common neurological disorder characterized by recurrent unprovoked seizures. Despite significant progress in epilepsy research, about 30% of patients continue to experience uncontrolled seizures and clear diagnostic criteria remain elusive. Abnormal glycosylation contributes to various neurological disorders, including Alzheimer's and Parkinson's diseases. However, it is unclear whether protein glycosylation is altered in epilepsy. Herein, we established a chronic epilepsy rat model by injecting kainic acid solution into the right lateral ventricle and examined the changes in protein N-glycosylation and O-GlcNAcylation in rat brain tissues using mass spectrometry and lectin blotting. We found a significant reduction in complex N-glycan abundance in the hippocampal tissue of epileptic rats, which may be related to decreased MGAT1 expression. Additionally, we observed a marked decrease in protein O-GlcNAcylation, which may be associated with reduced levels of GFPT1, the rate-limiting enzyme in the hexosamine biosynthesis pathway. This research offers new insight into potential therapeutic strategies for epilepsy.},
}

@article {pmid41315531,
year = {2025},
author = {George, JC and Tipton, AE and Bonfa, NVS and Farb, DH and Russek, SJ},
title = {Age-dependent increases in dorsal hippocampal postsynaptic α5GABA-a receptors may be lost in a rat model of Alzheimer's disease.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-025-28973-9},
pmid = {41315531},
issn = {2045-2322},
support = {NIGMS T32 GM008541, NIA R21AG056947, NIA R21AF061553-01//National Institutes of Health, United States/ ; NIA R21AG056947 NIH/NIA R21AF061553-01/NH/NIH HHS/United States ; },
}

@article {pmid41315482,
year = {2025},
author = {Park, S and Kim, K and Lim, KY and Na, DL and Kim, HJ and Jang, H and Kim, JP and Kang, SH and Yun, J and Chun, MY and Seo, SW and Kwak, K},
title = {Computed tomography-based nnU-Net for region-specific brain structural changes across the alzheimer's continuum and frontotemporal dementia subtypes.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {42597},
pmid = {41315482},
issn = {2045-2322},
support = {HU20C0111//Ministry of Health & Welfare and Ministry of Science and ICT, Republic of Korea/ ; NRF-2019R1A5A2027340//National Research Foundation of Korea/ ; 2021-ER1006-00//Research of Korea Disease Control and Prevention Agency/ ; },
mesh = {Humans ; *Frontotemporal Dementia/diagnostic imaging/pathology/cerebrospinal fluid ; *Alzheimer Disease/diagnostic imaging/pathology/cerebrospinal fluid ; Male ; Female ; Aged ; *Tomography, X-Ray Computed/methods ; *Brain/diagnostic imaging/pathology ; Middle Aged ; Magnetic Resonance Imaging ; Deep Learning ; Cognitive Dysfunction/diagnostic imaging/pathology ; Aged, 80 and over ; },
abstract = {Quantifying structural brain changes is critical for diagnosing and monitoring neurodegenerative diseases. Although magnetic resonance imaging (MRI) is the silver standard, limited accessibility and cost hamper routine use. We developed a deep learning-based framework using the nnU-Net for brain segmentation using computed tomography (CT) to assess cerebrospinal fluid (CSF) volume changes, as an indirect marker of tissue loss, and evaluated its utility across Alzheimer's disease (AD) stages and frontotemporal dementia (FTD) subtypes. We included 2357 participants: cognitively unimpaired (CU, n = 595), mild cognitive impairment (MCI, n = 954), dementia of Alzheimer's type (DAT, n = 663), and FTD subtypes (FTD, n = 145, behavioral variant FTD (bvFTD, n = 66), nonfluent variant primary progressive aphasia (nfvPPA, n = 29), and semantic variant PPA (svPPA, n = 50). CT-based segmentation was trained and validated using 3D T1-weighted MRI as reference. We assessed (1) segmentation accuracy via Dice similarity coefficients (DSCs), (2) reliability and precision using correlation and Bland-Altman analyses, and (3) clinical utility by identifying stage- and region-specific changes in CSF volumes. Key regions, including anterior and posterior lateral ventricles, showed DSCs above 0.93 and correlations ranging from 0.822 to 0.996. CT-based measurements revealed increasing CSF volumes from CU to DAT and distinct patterns of CSF volume enlargement across FTD subtypes. This framework enables accurate, reliable assessment of CSF volume changes as an indirect marker of atrophy, and supports early detection and differential diagnosis.},
}

Humans
*Frontotemporal Dementia/diagnostic imaging/pathology/cerebrospinal fluid
*Alzheimer Disease/diagnostic imaging/pathology/cerebrospinal fluid
Male
Female
Aged
*Tomography, X-Ray Computed/methods
*Brain/diagnostic imaging/pathology
Middle Aged
Magnetic Resonance Imaging
Deep Learning
Cognitive Dysfunction/diagnostic imaging/pathology
Aged, 80 and over

@article {pmid41315191,
year = {2025},
author = {Gao, R and Rao, S and Cheng, S and Gong, Z and Bu, B and Ba, L and Sun, X and Zhang, M},
title = {Assessing outer retinal and choroidal changes in scd: potential for high-risk screening using SS-OCTA.},
journal = {Translational psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41398-025-03781-x},
pmid = {41315191},
issn = {2158-3188},
abstract = {Subjective cognitive decline (SCD) serves as an initial symptom of preclinical Alzheimer's disease (AD). The accumulation of amyloid-beta (Aβ) is acknowledged as a critical risk factor for the eventual progression to mild cognitive impairment or dementia in individuals with SCD, highlighting the necessity for early detection and intervention. Previous studies have identified the retina and choriocapillaris as potential biomarkers for AD; however, these investigations have not thoroughly examined large and medium-sized choroidal vessels. Ultra-wide swept-source optical coherence tomography angiography (SS-OCTA), an innovative noninvasive imaging modality, facilitates rapid and precise quantitative assessment of retinal and choroidal boundaries and vasculature through dynamic scanning, encompassing large and medium-sized choroidal vessels. This study aims to characterize the outer retinal and choroidal vasculature and structure in individuals with SCD, examine the correlation between altered choroidal vasculature parameters and amyloid burden, and the presence of the apolipoprotein E (APOE) ε4 allele in SCD participants, to identify potential ocular biomarkers for high-risk SCD screening. In this study, 57 individuals with SCD and 45 matched normal controls were enrolled. Ultra-wide SS-OCTA was employed to assess the thickness of the outer retina and choroid and the blood flow within the choriocapillaris and large, medium-sized choroidal vessels. [18]F-Florbetapir positron emission tomography scans were performed to classify amyloid-positive-SCD (Aβ + SCD) and amyloid-negative-SCD (Aβ-SCD) groups. Plasma Aβ42/40 and APOE ε4 genotypes were also measured. Compared with normal controls, individuals with SCD exhibited a significant increase in the choroidal vessel index and a reduction in outer retinal thickness. The Aβ + SCD group demonstrated an elevated choriocapillaris flow area relative to the Aβ- SCD group. Moreover, a negative correlation was observed between the choriocapillaris flow area and plasma Aβ42/40 levels in the SCD cohort. Among SCD participants, APOE ε4 carriers displayed increased choriocapillaris flow area and choroidal vessel volume compared to APOE ε4 non-carriers. Our findings provide intriguing insights into the relationship between amyloid pathology and changes in the choriocapillaris flow area. The choroid may serve as a potential biomarker for screening Aβ + SCD.},
}

@article {pmid41315136,
year = {2025},
author = {Buzinova, VA and Johnson, CE and Turton, SM and Barth, SE and Padgett, S and Maisel, MT and Kohler, K and Whitlock, HR and Bachstetter, AD and Sunderam, S and O'Hara, BF and Duncan, MJ and Murphy, MP},
title = {Circadian rhythm of amyloid-β in the olfactory bulb and cerebellum of wild-type and APPxPS1 knock-in mice indicates a loss of rhythmicity in regions more vulnerable to amyloid pathology.},
journal = {Biogerontology},
volume = {27},
number = {1},
pages = {11},
pmid = {41315136},
issn = {1573-6768},
support = {AG078110//T32/ ; AG068215/NH/NIH HHS/United States ; },
mesh = {Animals ; *Circadian Rhythm/physiology ; *Olfactory Bulb/metabolism/pathology ; Male ; *Amyloid beta-Peptides/metabolism ; Female ; Mice, Transgenic ; Mice ; Gene Knock-In Techniques ; *Amyloid beta-Protein Precursor/genetics/metabolism ; *Cerebellum/metabolism/pathology ; *Alzheimer Disease/metabolism/pathology/genetics ; Disease Models, Animal ; *Presenilin-1/genetics/metabolism ; Mice, Inbred C57BL ; },
abstract = {Amyloid-β (Aβ) plaques are one of the primary biomarkers of Alzheimer's Disease (AD). Other publications have reported various mechanisms regarding the clearance of Aβ, and recent studies have also investigated the relationship between daily rhythms of Aβ and AD. The intent of this study was to determine if the circadian rhythm of Aβ differed between a region that was more vulnerable to AD-related pathology (the olfactory bulbs; OB) compared to a region that is less vulnerable (the cerebellum; CER). We chose to utilize an APPxPS1 knock-in (KI) mouse strain as this strain expresses amyloid precursor protein (APP) and Aβ under control of its normal promoter as opposed to AD transgenic models that overexpress APP and, as a consequence, Aβ. Mice (N = 128, equally divided between male and female, wild type and KI) were acclimated to a 12:12 light cycle for two weeks, and tissue was collected over a 24-h period in constant darkness. Using a unique immunoassay designed to measure human or rodent Aβ side-by-side, we confirmed a robust circadian Aβ rhythm in the mouse brain and that the OB contains more overall Aβ accumulation than the CER. The circadian Aβ rhythm was not present in the OB of the KI as compared to the WT mice. In contrast, the Aβ rhythm in the CER did not differ between genotypes. These results suggest that the loss of Aβ rhythm in disease-affected brain regions may be associated with the development of AD pathology and could have important implications for therapy.},
}

Animals
*Circadian Rhythm/physiology
*Olfactory Bulb/metabolism/pathology
Male
*Amyloid beta-Peptides/metabolism
Female
Mice, Transgenic
Mice
Gene Knock-In Techniques
*Amyloid beta-Protein Precursor/genetics/metabolism
*Cerebellum/metabolism/pathology
*Alzheimer Disease/metabolism/pathology/genetics
Disease Models, Animal
*Presenilin-1/genetics/metabolism
Mice, Inbred C57BL

@article {pmid41315132,
year = {2025},
author = {Lumsden, AL and Mulugeta, A and Hyppönen, E},
title = {Dementia risk across distinct metabolic profiles in the UK Biobank.},
journal = {GeroScience},
volume = {},
number = {},
pages = {},
pmid = {41315132},
issn = {2509-2723},
support = {GNT1157281//National Health and Medical Research Council/ ; MRF2007431//Medical Research Future Fund (AU)/ ; },
abstract = {Sub-optimal metabolism is linked to dementia risk, yet metabolic traits rarely occur in isolation. Using data from 308,019 UK Biobank participants, we examined associations of six diverse metabolic subgroups (I-VI) - previously derived via a self-organising map (SOM) that captures patterns of co-occurring metabolic biomarker traits in the population - and 39 individual biomarkers, with incident all-cause dementia, Alzheimer's disease (AD), and vascular dementia (VaD). Biomarker associations were assessed using both linear and nonlinear (restricted cubic spline) models. After adjusting for age, sex, socioeconomic, and lifestyle factors, subgroup analyses showed that participants in the two leanest and two most adipose subgroups had higher risk of dementia outcomes compared to others. Subgroups with high adiposity exhibited elevated VaD risk, which was linked to hypertension, hyperglycaemia, and liver stress (Subgroup II); inflammation, microalbuminuria, and low apolipoprotein A1 (III). For AD, the risk was elevated in the lean subgroups (IV, V), characterised by low body mass index (BMI), triglycerides, and urate, and high sex-hormone binding globulin; as well as for adipose Subgroup II. APOE-ε4 allele count had limited influence on dementia associations with metabolic subgroups and biomarkers. This marked metabolic heterogeneity in dementia risk suggests that metabolic profiling could inform targeted prevention strategies. Interpretation of these findings is supported by previously reported MRI profiles of the metabolic subgroups, providing biological context.},
}

@article {pmid41315049,
year = {2025},
author = {Bolton, CJ and Zhang, P and Wilhoite, SR and Moore, EE and Houston, ML and Pechman, KR and Dumitrescu, L and Peterson, A and Khan, OA and Liu, D and Gifford, KA and Blennow, K and Hohman, TJ and Zetterberg, H and Jefferson, AL},
title = {Increased neuroplastic activity in the pathogenesis of Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {11},
pages = {e70897},
doi = {10.1002/alz.70897},
pmid = {41315049},
issn = {1552-5279},
support = {IIRG-08-88733/ALZ/Alzheimer's Association/United States ; P20-AG068082/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *Alzheimer Disease/cerebrospinal fluid/genetics/physiopathology/pathology ; Female ; Male ; Aged ; Amyloid beta-Peptides/cerebrospinal fluid ; *GAP-43 Protein/cerebrospinal fluid ; tau Proteins/cerebrospinal fluid ; *Neuronal Plasticity/physiology ; Biomarkers/cerebrospinal fluid ; Cross-Sectional Studies ; Longitudinal Studies ; Peptide Fragments/cerebrospinal fluid ; Aged, 80 and over ; Risk Factors ; Middle Aged ; Cognitive Dysfunction/cerebrospinal fluid ; Apolipoprotein E4/genetics ; },
abstract = {INTRODUCTION: We test the hypothesis that high levels of neuroplasticity in the context of Alzheimer's disease (AD) risk factors are involved in AD pathogenesis by investigating interactions between cerebrospinal fluid (CSF) levels of growth-associated protein-43 (GAP-43) and AD risk factors (female sex, cerebrovascular risk, mild cognitive impairment, apolipoprotein E [APOE] ε4 genotype, amyloid positivity) on CSF biomarkers of AD pathology (amyloid beta 42/40[Aβ42/40], phosphorylated tau (p-tau)) and neurodegeneration (tau).

METHODS: Baseline GAP-43 levels in 161 non-demented older adults were related to cross-sectional and longitudinal (mean follow-up = 4 years) CSF biomarkers of AD, adjusting for covariates, with GAP-43 x AD risk factor interaction terms.

RESULTS: Higher GAP-43 was cross-sectionally related to all AD biomarkers (p-values < 0.0001) and predicted longitudinal reductions in Aβ42 (p < 0.0001). Associations were stronger in AD risk groups.

DISCUSSION: We found strong support linking increased levels of neuroplasticity in the context of AD risk factors to the pathological cascade of AD over a 4-year mean follow-up period.

HIGHLIGHTS: Cerebrospinal fluid growth-associated protein-43 (GAP-43) is associated with Alzheimer's disease (AD) biomarkers cross-sectionally and longitudinally. GAP-43 interacts with AD risk factors to predict AD biomarkers. Increased neuroplastic activity may play a role in AD pathogenesis.},
}

Humans
*Alzheimer Disease/cerebrospinal fluid/genetics/physiopathology/pathology
Female
Male
Aged
Amyloid beta-Peptides/cerebrospinal fluid
*GAP-43 Protein/cerebrospinal fluid
tau Proteins/cerebrospinal fluid
*Neuronal Plasticity/physiology
Biomarkers/cerebrospinal fluid
Cross-Sectional Studies
Longitudinal Studies
Peptide Fragments/cerebrospinal fluid
Aged, 80 and over
Risk Factors
Middle Aged
Cognitive Dysfunction/cerebrospinal fluid
Apolipoprotein E4/genetics

@article {pmid41314835,
year = {2025},
author = {Murad-Kassam, S and O'Rourke, HM and Hunter, K and Tate, K and Salma, J},
title = {Exploring the hospitalisation experience of racialised older adults and caregivers living with dementia: a scoping review protocol.},
journal = {BMJ open},
volume = {15},
number = {11},
pages = {e096069},
doi = {10.1136/bmjopen-2024-096069},
pmid = {41314835},
issn = {2044-6055},
mesh = {Humans ; Scoping Review as Topic ; *Dementia/therapy/psychology/ethnology ; *Caregivers/psychology ; *Hospitalization/statistics & numerical data ; Aged ; Research Design ; Quality of Life ; *Racism ; },
abstract = {INTRODUCTION: Racialised older adults living with dementia face various challenges and barriers in receiving culturally sensitive care in hospital settings. Stigma, discrimination and healthcare provider bias toward racialised older adults living with dementia infringe on their right to access quality care services in acute hospital settings and can negatively affect their quality of life. Despite the growing need to integrate culturally sensitive dementia care into acute hospital care, little research has been done in this area. Therefore, the aim of this scoping review is to summarise and map what is known about the hospitalisation experience of racialised older adults with dementia in receiving care and identify research gaps.

METHOD AND ANALYSIS: We will use Arksey and O'Malley's framework and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews checklist to conduct and write the review. The search strategy will use keywords and index terms across selected databases: Google Scholar, PubMed, Scopus, Medline, PsycINFO and Cumulative Index for Nursing and Allied Health Literature, and hand-searching the reference lists from chosen literature. Grey literature will be searched using Google and the Alzheimer Society websites to find further evidence and literature. Two researchers will screen the titles and abstracts independently by referring to the inclusion criteria. Data from the extracted studies will be reported in tabular and narrative form that answer the scoping review's questions. Research gaps and recommendations for future research will be identified and summarised. The review's results will be shared with stakeholders, policymakers, healthcare professionals and community organisations working with the racialised community and dementia care.

ETHICS AND DISSEMINATION: This scoping review does not require ethics approval because it collects data from publicly available resources. The results will be disseminated through peer-reviewed scientific journals, professional conferences and with community organisations and healthcare providers.

REGISTRATION DETAILS: This review is registered in the Open Science Framework registration link: osf.io/7rfje.},
}

Humans
Scoping Review as Topic
*Dementia/therapy/psychology/ethnology
*Caregivers/psychology
*Hospitalization/statistics & numerical data
Aged
Research Design
Quality of Life
*Racism

@article {pmid41314755,
year = {2025},
author = {Roy, K and Syed, M and Narad, P and Sengupta, A},
title = {Genetic and epigenetic drivers of neurodegenerative disorders.},
journal = {Progress in brain research},
volume = {297},
number = {},
pages = {53-130},
doi = {10.1016/bs.pbr.2025.08.002},
pmid = {41314755},
issn = {1875-7855},
mesh = {Humans ; *Neurodegenerative Diseases/genetics ; *Epigenesis, Genetic/genetics ; Animals ; },
abstract = {Neurodegenerative illnesses such as Alzheimer's disease, Parkinson's disease, and Huntington's disease present with increasing neurodegeneration and derangement. Genomic mutations and epigenetic changes are known to be part of their causation. This particular chapter discusses the key genetic factors like APP, SNCA, HTT, and C9orf72 mutations that influence the development and course of the disease. Furthermore, we examine epigenetic mechanisms-DNA methylation, histone modification, and non-coding RNAs-that regulate gene expression and contribute to neuronal susceptibility. The discussion also focuses on environmental and behavioral factors that affect the epigenome, highlighting gene-environment interactions. Advancements in omics technology and integrative studies have enhanced comprehension of biological pathways and uncovered novel biomarkers and therapeutic targets. The chapter therefore integrates epigenetic and genetic viewpoints to elucidate the intricate regulatory processes responsible for neurodegeneration and highlights potential avenues for early diagnosis, precision medicine, and therapeutic interventions aimed at remodeling disease pathways.},
}

Humans
*Neurodegenerative Diseases/genetics
*Epigenesis, Genetic/genetics
Animals

@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 {pmid41314748,
year = {2025},
author = {Quadri, SN and Tiwari, S and Siddiqi, B and Fatima, S and Khan, MA and Abdin, MZ},
title = {Advanced neuroimaging in precision neurology: Tools, trends, and translational impact.},
journal = {Progress in brain research},
volume = {297},
number = {},
pages = {221-246},
doi = {10.1016/bs.pbr.2025.08.005},
pmid = {41314748},
issn = {1875-7855},
mesh = {Humans ; *Neuroimaging/methods/trends ; *Neurodegenerative Diseases/diagnostic imaging ; *Precision Medicine/methods/trends ; Translational Research, Biomedical ; *Neurology/methods/trends ; Artificial Intelligence ; Machine Learning ; },
abstract = {Advances in neuroimaging are revolutionizing the landscape of precision neurology by enabling high-resolution, multimodal visualization of brain structure, function, and pathology. As traditional, symptom-based frameworks fall short in capturing the biological complexity of neurodegenerative diseases, imaging modalities such as structural MRI, diffusion tensor imaging, functional MRI, PET, and hybrid PET/MRI have emerged as essential tools for early diagnosis, patient stratification, and therapeutic monitoring. These technologies not only reveal hallmark features like hippocampal atrophy and disrupted neural networks but also uncover molecular signatures such as amyloid and tau deposition, synaptic density, and neuroinflammation. Integration with artificial intelligence (AI) and machine learning (ML) further enhances diagnostic precision by decoding subtle imaging patterns, facilitating subtype classification, and predicting disease progression. Despite transformative progress, disparities in access and implementation remain a critical challenge, particularly in low- and middle-income countries. This chapter provides a comprehensive overview of neuroimaging modalities, their diagnostic and prognostic relevance across major neurodegenerative conditions including Alzheimer's disease, Parkinson's disease, ALS, and frontotemporal dementia and the evolving role of hybrid platforms and AI integration in shaping the future of individualized neurological care.},
}

Humans
*Neuroimaging/methods/trends
*Neurodegenerative Diseases/diagnostic imaging
*Precision Medicine/methods/trends
Translational Research, Biomedical
*Neurology/methods/trends
Artificial Intelligence
Machine Learning

@article {pmid41314746,
year = {2025},
author = {Ceballos, MWG and Sy, FFA and Akbar, A and Taofiq, A},
title = {Multi-omics integration in disease research.},
journal = {Progress in brain research},
volume = {297},
number = {},
pages = {155-189},
doi = {10.1016/bs.pbr.2025.08.012},
pmid = {41314746},
issn = {1875-7855},
mesh = {Humans ; *Neurodegenerative Diseases/genetics/metabolism ; *Proteomics/methods ; *Genomics/methods ; *Metabolomics/methods ; Animals ; Multiomics ; },
abstract = {Neurodegenerative diseases, marked by complex molecular mechanisms and diverse clinical features, challenge conventional research approaches. This chapter emphasizes the value of multi-omics integration in understanding the biology of Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis (ALS). Genomic studies reveal risk variants such as APOE ε4 in Alzheimer's and rare mutations in familial forms. Transcriptomics highlights gene expression changes, including synaptic dysfunction in early Parkinson's and alternative splicing errors in TARDBP-related ALS. Proteomics identifies key protein aggregates like amyloid beta and alpha-synuclein, along with modifications such as hyperphosphorylated tau that correlate with cognitive decline. Metabolomics uncovers metabolic alterations, including mitochondrial dysfunction in Parkinson's and lipid peroxidation in ALS, which contribute to disease progression. By combining these layers with high-throughput tools like single-cell sequencing, spatial transcriptomics, and mass spectrometry, researchers can reconstruct molecular networks linking genetic risk, gene regulation, protein dysfunction, and metabolic imbalance. This approach enables patient stratification into molecular subtypes, such as neuroinflammatory clusters defined by microglial gene signatures and cytokine expression. Biomarkers from blood and cerebrospinal fluid allow for minimally invasive disease monitoring. Despite challenges such as data heterogeneity and limited standardization, multi-omics approaches support biomarker discovery and therapeutic development. Integrating these datasets with neuroimaging and digital tools enhances diagnostic precision and guides targeted interventions, such as antisense therapies for SOD1-linked ALS. Multi-omics integration is thus a critical foundation for advancing personalized strategies in neurodegenerative disease research.},
}

Humans
*Neurodegenerative Diseases/genetics/metabolism
*Proteomics/methods
*Genomics/methods
*Metabolomics/methods
Animals
Multiomics

@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 {pmid41314634,
year = {2025},
author = {Verde, ASSL and Morais, ABCG and Catunda, AV and Landim, JID and Ribeiro, IS and Iepsen, BD and Frota, NAF},
title = {Cerebrospinal fluid biomarkers in cerebral amyloid angiopathy: insights from a clinical case series.},
journal = {Arquivos de neuro-psiquiatria},
volume = {83},
number = {12},
pages = {1-6},
doi = {10.1055/s-0045-1812887},
pmid = {41314634},
issn = {1678-4227},
mesh = {Humans ; *Cerebral Amyloid Angiopathy/cerebrospinal fluid/diagnosis/diagnostic imaging ; Biomarkers/cerebrospinal fluid ; Male ; *Amyloid beta-Peptides/cerebrospinal fluid ; Female ; Aged ; Middle Aged ; Aged, 80 and over ; Peptide Fragments/cerebrospinal fluid ; tau Proteins/cerebrospinal fluid ; Magnetic Resonance Imaging ; },
abstract = {Cerebral amyloid angiopathy (CAA) is a small vessel disease characterized by the deposition of amyloid-beta in small cerebral vessels, which can lead to intracerebral hemorrhages and cognitive impairment. Rare variants, such as cerebral amyloid angiopathy-related inflammation (CAA-ri) and iatrogenic CAA (ICAA), may mimic other neurological conditions and challenge diagnosis in clinical practice. We present three cases that illustrate distinct CAA syndromes, along with CSF biomarker analysis. One patient experienced recurrent hemorrhagic strokes with a history of dural graft, raising concerns about amyloid transmission. Two patients presented with rapidly progressive dementia that fulfilled CAA-ri criteria. All cases exhibited decreased levels of CSF Aβ40 and Aβ42, with one showing elevated p-tau, suggesting comorbid Alzheimer's pathology. Cerebrospinal fluid biomarkers complement neuroimaging in the diagnosis of CAA, aiding in differentiation from other dementias. Early recognition and diagnosis of CAA-ri variants is crucial, because immunotherapy may improve outcomes. Further research is necessary to establish biomarker thresholds and their clinical applicability.},
}

Humans
*Cerebral Amyloid Angiopathy/cerebrospinal fluid/diagnosis/diagnostic imaging
Biomarkers/cerebrospinal fluid
Male
*Amyloid beta-Peptides/cerebrospinal fluid
Female
Aged
Middle Aged
Aged, 80 and over
Peptide Fragments/cerebrospinal fluid
tau Proteins/cerebrospinal fluid
Magnetic Resonance Imaging

@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 {pmid41314550,
year = {2025},
author = {Liang, B and Li, M and Zhang, L},
title = {Identification of endoplasmic reticulum stress-related genes associated with Alzheimer's disease risk: A multi-omics Mendelian randomization analysis.},
journal = {Journal of affective disorders},
volume = {},
number = {},
pages = {120770},
doi = {10.1016/j.jad.2025.120770},
pmid = {41314550},
issn = {1573-2517},
abstract = {BACKGROUND: Endoplasmic Reticulum (ER) stress is implicated in Alzheimer's disease (AD) development. This study aims to identify ER stress-related genes associated with AD risk.

METHODS: This study used a multi-omics framework based on Summary-data-based Mendelian Randomization (SMR) to investigate associations between ER stress-related genes and AD. Blood-derived quantitative trait loci (QTL) datasets, including methylation (mQTL), expression (eQTL), and protein (pQTL) data, were integrated with AD genome-wide association study (GWAS) results from FinnGen R12 (discovery) and GCST90027158 (validation). Colocalization and multi-omics integration analyses identified shared variants and regulatory relationships. Brain tissue eQTL data from GTEx were used for validation.

RESULTS: SMR analysis identified 245 mQTLs, 29 eQTLs, and 7 pQTLs associated with AD risk. The Tier 1 gene CHRNE showed consistent positive associations across blood and brain eQTL analyses, implicating cholinergic dysfunction in AD susceptibility. The Tier 2 gene CHMP1A was associated with AD across all three regulatory layers, suggesting that reduced expression of this endosomal sorting and autophagy-related protein may disrupt proteostasis and increase AD risk. The Tier 3 genes GRINA and ATP2A1 were validated across mQTL and eQTL analyses, indicating that reduced expression of these calcium homeostasis regulators may aggravate ER stress-related neuronal injury.

CONCLUSIONS: Our study provides genetic evidence supporting the involvement of ER stress in AD through a multi-omics SMR framework. The findings highlight three major pathogenic pathways underlying AD susceptibility: cholinergic dysfunction mediated by CHRNE, proteostasis imbalance linked to CHMP1A, and calcium signaling disruption driven by GRINA and ATP2A1. These results not only offer new insights into the molecular mechanisms of AD but also identify high-confidence targets for precision therapeutic development focused on ER stress regulation.},
}

@article {pmid41314512,
year = {2025},
author = {Motsenyat, A and Zhong, XZ and Van Lankveld, H and Chen, JX and Mathew, A and Chen, JJ},
title = {Modulating cerebrospinal fluid dynamics using pulsed photobiomodulation.},
journal = {Brain stimulation},
volume = {},
number = {},
pages = {102988},
doi = {10.1016/j.brs.2025.102988},
pmid = {41314512},
issn = {1876-4754},
abstract = {INTRODUCTION: The use of photobiomodulation (PBM) to enhance brain health, specifically glymphatic drainage and thus neurotoxic waste clearance, may make it a promising therapeutic tool against neurodegenerative diseases such as Alzheimer's disease.

MATERIAL AND METHOD: This study investigates whether PBM can modulate cerebrospinal fluid (CSF) flow in 45 healthy young adults. We conducted forehead transcranial PBM (tPBM) and intranasal PBM (iPBM) at the nostril, and measured CSF dynamics using blood-oxygenation level-dependent (BOLD) functional MRI (fMRI). Our data demonstrates 4 min of PBM-induced increases in CSF flow.

CONCLUSION AND RESULT: Our data shows that (1) even a short PBM of 4 min can induce a change in CSF dynamics, in the form of an immediate increase in intracranial CSF volume and a reduction in CSF inflow; (2) skin melanin had a significant effect on the CSF response in tPBM, with lighter skin associated with higher responses; (3) both iPBM and tPBM displayed a dose-dependent effect on CSF dynamics in terms of a wavelength-irradiance interaction; (4) intranasal PBM (iPBM) can be used to produce a significant change in CSF dynamics that is equivalent to forehead transcranial PBM (tPBM) with a small fraction of the irradiance. The most likely explanation for the observed fMRI signal changes in CSF regions of interest for both tPBM and iPBM is an increased CSF outflow pressure due to PBM-induced vasodilation that transiently increases intracranial CSF volume and reduces net CSF inflow.

IMPACT: This study establishes that PBM can modulate CSF flow in the healthy human brain in real time. This study also suggests that iPBM may be more efficient in CSF modulation due to the proximity to the olfactory system and the lack of melanin dependence. The influence of melanin on tPBM, the feasibility of iPBM and the dose dependence of both will require further investigation in healthy and patient populations.},
}

@article {pmid41314505,
year = {2025},
author = {Pratap, GK and Pramoda, GN and Joshi, CG and Sannegowda, LK and Shantaram, M and Priyadarshini, P},
title = {Structure-function characterization of olea dioica PGK-1: Acetylcholinesterase inhibition, molecular docking, and amelioration of Aβ42-induced toxicity in SH-SY5Y neuronal cells and the UAS-Aβ42; ey-GAL4 drosophila model of Alzheimer's disease.},
journal = {Neuroscience letters},
volume = {},
number = {},
pages = {138467},
doi = {10.1016/j.neulet.2025.138467},
pmid = {41314505},
issn = {1872-7972},
}

@article {pmid41314458,
year = {2025},
author = {Pavlin, D and Hlebec, V and Doušak, M and Pipan, MZ},
title = {The Hidden Cost of Caring: Psychological Burden Among Caregivers of Dogs with Cognitive Dysfunction, Cancer, and Age-Related Decline.},
journal = {Veterinary journal (London, England : 1997)},
volume = {},
number = {},
pages = {106510},
doi = {10.1016/j.tvjl.2025.106510},
pmid = {41314458},
issn = {1532-2971},
abstract = {Canine cognitive dysfunction (CCD) is a neurodegenerative disorder like Alzheimer's disease in humans, but its impact on caregivers is poorly understood. This study examines the multidimensional burden of caregivers of ageing dogs, comparing caregivers of healthy ageing dogs (HAD), dogs with chronic oncological disease (COD) and dogs with CCD. In a cross-sectional survey of 516 Slovenian dog owners, seven areas of stress were investigated: time burden, work- life interference, emotional burden, social stigmatization, financial burden, perceived adequacy of care and veterinary support. Time burden was increased by unpredictable CCD symptoms (e.g. nocturnal restlessness, disorientation), especially in households with children or multiple pets (p=0.005). Emotional distress was significantly increased in CCD caregivers due to feelings of stigmatization (p=0.005), while COD caregivers reported no significant increase compared to HAD. Caregivers of dogs with CCD reported significantly greater stigmatization (p < 0.001) and financial burden (p < 0.001). While all groups reported similar perceived inadequacies in care, CCD caregivers expressed significantly lower confidence in performing positive care tasks (p = 0.041). Relationships with veterinarians did not differ between groups, although regression analysis identified age, education and number of pets as predictors of the dynamics between caregivers and veterinarians. This study shows that caring for dogs with CCD is significantly more stressful than caring for healthy older dogs and, in several areas, caring for dogs with chronic oncologic diseases. The results emphasize that caring for dogs with CCD is a complex, underestimated burden that is comparable to caring for dementia patients in humans and requires targeted interventions.},
}

@article {pmid41310741,
year = {2025},
author = {Calon, F},
title = {The duality of the BBB: breaking the myth of the blood-brain barrier breakdown.},
journal = {Fluids and barriers of the CNS},
volume = {22},
number = {1},
pages = {120},
pmid = {41310741},
issn = {2045-8118},
support = {FRQ-S, #253895//Fonds de la recherche du Québec/ ; PJT 168927, PJT 183735/CAPMC/CIHR/Canada ; },
abstract = {Research on the blood-brain barrier (BBB) has greatly evolved over the past 20 years, with growing recognition of its role as a multicellular complex regulating brain homeostasis. Previously confined to pharmaceutical sciences, the BBB has now become a growing focus of interest for neuroscientists and clinicians. However, the word ‘barrier’, implying something that can be broken, opened, or disrupted, can lead to confusion when one tries to relate this concept to its underlying cell biology. Here, echoing the fundamental question posed by Lina Stern when she first defined the BBB in 1921, I suggest that the confusion stems from conflating the physicochemical properties intrinsic to the barrier with the living biological multicellular interface. Notwithstanding its complexity, the BBB is now often simplistically portrayed as “permeable”, particularly in the context of prevalent diseases, such as Alzheimer’s, depression, multiple sclerosis, or stroke. Such overly simplified concepts promoted over the past two decades have led to misconceptions that hinder a proper understanding of the BBB, affecting both the general public and seasoned scientists. This misunderstanding is not without harmful clinical impact as many interpret the BBB as something that often breaks, leading to a massive entry of drugs and other blood-borne compounds into the brain, which is very rarely the case. After outlining the likely causes of these misconceptions and trying to define the concepts of “BBB permeability” and “brain bioavailability”, I offer several recommendations: (1) more frequent use of quantitative methods involving small hydrophilic compounds to measure BBB integrity; (2) avoid terms such as ‘BBB disruption,’ ‘opening,’ or ‘breakdown,’ and instead favor terms like ‘dysfunction’ or, where appropriate, ‘leakage’, essentially when describing biological defects assessed by changes in large molecule localization; and (3) always account for the dual nature of the BBB, as both a physicochemical barrier and a living biological interface.},
}

@article {pmid41314452,
year = {2025},
author = {Afify, AM and El-Sayed, EK and Ismail, A and Nofal, S},
title = {Nanocarrier-Enhanced Simvastatin Modulates AMPK-ULK1 Pathway and Oxidative Stress in Alzheimer's Disease Model.},
journal = {European journal of pharmacology},
volume = {},
number = {},
pages = {178411},
doi = {10.1016/j.ejphar.2025.178411},
pmid = {41314452},
issn = {1879-0712},
abstract = {In Alzheimer's disease (AD), the hippocampus and cerebral cortex are primarily affected, showing degeneration of cholinergic neurons and Aβ plaques accumulation. These changes are strongly associated with oxidative stress, neuroinflammation, and impaired autophagy. In our study simvastatin (Simva), a lipid-lowering statin, was investigated against aluminum chloride (AlCl3)-induced rat model of AD and showed potential neuroprotective effects. Nano-delivery systems were used to enhance Simva's brain pharmacological activity. Adult male Sprague Dawley rats were designated into four groups: Control group (normal saline, IP, 28 days), AlCl3 group (25 mg/ kg AlCl3, IP for 28 days), Simva group (Simva 10 mg/kg, orally for 28 days 1 hr before AlCl3 injection) and Simva-Nano group (Simva nanocarrier 10mg/kg, orally for 28 days 1 hr before AlCl3 injection). Simva and its nanocarrier enhanced autophagy by upregulating p-AMPK, p-ULK1, and LC3-II while downregulating ULK1. They showed strong antioxidant and anti-inflammatory effects by decreasing MDA, TNF-α, IL-1β and increased GSH. Additionally, they increased ACh levels and suppressed AChE gene expression. Immunohistochemical staining revealed substantial reduction in Aβ plaques in the Simva group, while in Simva-Nano group, Aβ plaques were not detected under our assay conditions. Aβ immunostaining was quantified as the number of Aβ deposits per field (6 fields). Histopathological analysis confirmed reduced neuronal degeneration and glial activation, with the Simva-Nano group demonstrating near-normal hippocampal architecture. In conclusion, Simva exhibits notable neuroprotective effects in the AD rat model via antioxidative, anti-inflammatory, and autophagic pathways. Nanocarrier delivery further improves Simva's pharmacological effects, offering a promising AD therapeutic strategy.},
}

@article {pmid41314410,
year = {2025},
author = {Breithaupt, AG and Tang, A and Paolillo, EW and Bibars, M and Johnson, ECB and Saloner, R and Possin, KL and Windon, CC and Hill-Jarrett, TG and Giorgio, J and Rauschecker, AM and Kwon, H and Vonk, JMJ and Pinheiro-Chagas, P},
title = {Review of Artificial Intelligence for Clinical Use in Alzheimer's Disease and Related Dementias.},
journal = {Seminars in neurology},
volume = {},
number = {},
pages = {},
doi = {10.1055/a-2744-9871},
pmid = {41314410},
issn = {1098-9021},
support = {K23AG093166//National Institute on Aging of the National Institutes of Health/ ; },
abstract = {As the U.S. population ages, Alzheimer's disease and related dementias (ADRD) cases are increasing, resulting in long wait times for specialist care. We review state-of-the-art artificial intelligence (AI) applications in ADRD care, from streamlining clinical diagnosis to pioneering novel digital biomarkers. Near-term AI applications include neuroimaging interpretation, conversational agents for patient interviews, and digital cognitive assessments. Large language models show promise as collaborative partners, helping clinicians interpret complex data while supporting patients and caregivers. Emerging digital biomarkers-speech analysis, passive monitoring through wearable devices, electronic health record analysis, and multiomics-offer potential for continuous monitoring to detect cognitive decline years before traditional assessments. Despite the acceleration of AI innovation, most of these systems are inaccessible in clinical practice. Implementation bottlenecks include limited external validation, technical challenges, model biases, infrastructure, and regulatory requirements. This review aims to help neurologists navigate this rapidly evolving AI landscape and prepare for implementation in ADRD care.},
}

@article {pmid41314271,
year = {2025},
author = {Chen, J and Jiang, Z and Coughlin, JM and Cheong, I and Mills, KA and Pomper, MG and Du, Y},
title = {Deep learning-derived arterial input function for dynamic brain PET.},
journal = {NeuroImage},
volume = {},
number = {},
pages = {121609},
doi = {10.1016/j.neuroimage.2025.121609},
pmid = {41314271},
issn = {1095-9572},
abstract = {Dynamic positron emission tomography (PET) imaging combined with radiotracer kinetic modeling is a powerful technique for visualizing biological processes in the brain, offering valuable insights into brain functions and neurological disorders such as Alzheimer's and Parkinson's diseases. Accurate kinetic modeling relies heavily on the use of a metabolite-corrected arterial input function (AIF), which typically requires invasive and labor-intensive arterial blood sampling. While alternative non-invasive approaches have been proposed, they often compromise accuracy or still necessitate at least one invasive blood sampling. In this study, we present the deep learning-derived arterial input function (DLIF), a deep learning framework capable of estimating a metabolite-corrected AIF directly from dynamic PET image sequences without any blood sampling. We validated DLIF using existing dynamic PET patient data. We compared DLIF and resulting parametric maps against ground truth measurements. Our evaluation shows that DLIF achieves accurate and robust AIF estimation. By leveraging deep learning's ability to capture complex temporal dynamics and incorporating prior knowledge of typical AIF shapes through basis functions, DLIF provides a rapid, accurate, and entirely non-invasive alternative to traditional AIF measurement methods.},
}

@article {pmid41314266,
year = {2025},
author = {Shen, S and Zheng, Y and Xie, Y and You, X and Chen, X and Xie, B and Weng, J and Huo, Q and Zhang, Y and Meselhy Zayed, MR and Yan, Q},
title = {Rocket-inspired gas-propelled microneedles engineered with borneol-NLCs-loaded hierarchical cavities for enhanced brain delivery in Alzheimer's therapy.},
journal = {International journal of pharmaceutics},
volume = {},
number = {},
pages = {126418},
doi = {10.1016/j.ijpharm.2025.126418},
pmid = {41314266},
issn = {1873-3476},
abstract = {Microneedle technology has emerged as a promising transdermal platform for transdermal delivery of Alzheimer's disease therapeutics. However, conventional passive diffusion approaches face fundamental limitations in overcoming both skin and blood-brain barriers. To address these limitations, we developed a rocket-inspired gas-propelled microneedle system integrating nanostructured lipid carriers for enhanced dual-barrier penetration. The study combined fluid vortex generation with blood-brain barrier endothelial remodeling to achieve efficient drug delivery. Specifically, the system featured a hierarchical cavity design with borneol-modified huperzine A-loaded nanostructured lipid carriers (NLCs) (particle size: 89.6 ± 0.7 nm; zeta potential: -22.5 ± 0.5 mV; Hup A encapsulation efficiency: 83.40 ± 1.51 %; drug loading capacity: 2.63 ± 0.06 %) in primary cavities and a spatially isolated pneumatic initiator (ascorbic acid/sodium bicarbonate) in secondary cavities. Through multiphysics simulation coupled fluid dynamics with chemical reaction kinetics and mass transport phenomena, which revealed that acid-base reactions generate CO2 microbubbles capable of producing rapid thrust forces. This microbubble-mediated propulsion mechanism achieved a 50 % increase in penetration depth (up to ∼ 1428 µm) relative to conventional microneedle platforms. Remarkably, this innovative hierarchical cavity design achieved a high drug loading capacity of 182 μg/array while preserving spatial isolation between the reactants and therapeutic payload. In vivo studies validated efficient brain delivery, as evidenced by a marked increase (p < 0.001) in cortical acetylcholine concentrations and amelioration of scopolamine-induced spatial memory impairments in rat models. This work established a preclinical proof-of-concept for the enhanced brain delivery of therapeutics in neurodegenerative disease through the synergistic integration of gas-propulsion physics and advanced nanocarrier engineering, offering new possibilities for overcoming biological delivery barriers.},
}

@article {pmid41314255,
year = {2025},
author = {Odonchimed, S and Imamura, K and Inoue, H},
title = {Neurodegenerative Disease and Autophagy in iPSC models.},
journal = {Neuroscience research},
volume = {},
number = {},
pages = {104991},
doi = {10.1016/j.neures.2025.104991},
pmid = {41314255},
issn = {1872-8111},
abstract = {Neurodegenerative diseases are characterized by the gradual deterioration of specific neuronal populations, ultimately resulting in motor, cognitive, or behavioral impairments. Despite the worldwide increase in disease incidence, effective therapies remain unavailable. A common pathological hallmark of neurodegenerative diseases is the accumulation of misfolded protein aggregates, which impair normal cellular function. Accordingly, numerous studies and therapeutic strategies have focused on targeting these toxic aggregates and protein quality control via autophagy, a vital cellular recycling mechanism. Autophagy dysregulation has been implicated in the pathogenesis of several neurodegenerative diseases. Induced pluripotent stem cell (iPSC) technology has emerged as a powerful platform for modeling neurodegenerative diseases, and iPSC-derived models provide human-relevant systems for studying autophagic dysfunction in vitro. In this review, we discuss the key findings of recent studies investigating autophagy in iPSC-based models of neurodegenerative diseases, including Alzheimer's disease, amyotrophic lateral sclerosis, frontotemporal dementia, and other diseases.},
}

@article {pmid41314100,
year = {2025},
author = {Sharma, D and Ravi, RN and Abdullah, ADI and Subramaniyan, V},
title = {Therapeutic prospects of modulating TLR4/MAPK/ROS signalling in obesity-associated neuroinflammation.},
journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie},
volume = {193},
number = {},
pages = {118805},
doi = {10.1016/j.biopha.2025.118805},
pmid = {41314100},
issn = {1950-6007},
abstract = {It is becoming more widely acknowledged that obesity is a chronic low-grade inflammatory disease that has a significant influence on brain health in addition to metabolic problems. Adipose tissue growth, macrophage polarization, and cytokine release all contribute to systemic inflammation, which weakens the blood-brain barrier (BBB) and promotes immune-to-brain communication. Saturated fatty acids and gut-derived lipopolysaccharides activate Toll-like receptor 4 (TLR4) in the central nervous system, which triggers downstream nuclear factor-κB (NF-κB) and Mitogen-activated protein kinase (MAPK) cascades and increases neuroinflammation. At the same time, mitochondrial malfunction and oxidative stress hasten the buildup of reactive oxygen species (ROS), which further primes the NOD-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome and maintains glial hyperactivation. These processes work together to cause synaptic dysfunction, insulin resistance in neurons, and heightened susceptibility to neurodegenerative illnesses, including Parkinson's and Alzheimer's. Pharmacological inhibitors, natural substances, and lifestyle changes that target TLR4, MAPK signaling, and ROS-mediated pathways have the potential to disrupt this metabolic-inflammatory-neuronal axis. Developing comprehensive solutions to reduce obesity-driven neuroinflammation requires an understanding of the molecular interactions between peripheral metabolic stress and central immune activation.},
}

@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 {pmid41313964,
year = {2025},
author = {Liu, W and Wu, L and Zeng, X and Chen, H and Ning, X and Sun, X and Xuan, W and Hao, Y and Jia, H and Li, Z and Xu, Z and Li, X and Xu, Z and Liu, W and Zhao, Q and Hao, S},
title = {Discovery of novel harmine derivatives as potent, selective, and brain permeable GSK3β inhibitors with effective In vivo anti-AD activity.},
journal = {European journal of medicinal chemistry},
volume = {303},
number = {},
pages = {118389},
doi = {10.1016/j.ejmech.2025.118389},
pmid = {41313964},
issn = {1768-3254},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder with limited therapeutic options. Glycogen synthase kinase 3β (GSK3β), a key enzyme in tau phosphorylation, is a promising therapeutic target for AD. Herein, we employed a structure-based drug design strategy to develop a novel series of harmine derivatives as potent GSK3β inhibitors. Among them, compound 39a bearing an intramolecular hydrogen bond scaffold, showed potent GSK3β inhibition (IC50 = 0.37 nM), meanwhile maintaining remarkable kinase selectivity, including >25000-fold selectivity over dual specificity tyrosine phosphorylation regulated kinase 1A (DYRK1A), a well-known target of β-carboline derivative harmine. It suppressed tau phosphorylation in Tau (P301L) 293T cells (EC50 = 0.06 ± 0.01 μM) and exhibited favorable blood-brain barrier permeability. Notably, 39a significantly attenuated cognitive deficits and tau hyperphosphorylation pathology in OA-induced C57BL/6J mice and 3 × Tg-AD mouse models, without causing spontaneous locomotor defects at therapeutic doses. Collectively, 39a emerges as a promising GSK3β inhibitor for probing GSK3β's role in AD pathogenesis and guiding anti-AD drug discovery.},
}

@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 {pmid41313780,
year = {2025},
author = {Li, L and Jia, M and Yang, C and Zhao, Y and Hu, J and Zhao, Y and Hu, X and Ning, F and Ding, C and Li, Q and Gong, J and Jia, X and Xu, K and Wang, Y and Zhou, S and Deng, L and Shi, L and Chen, X and Liu, X and Liu, Z},
title = {Gut microbial-derived indole-3-propionate improves cognitive function in Alzheimer's disease.},
journal = {Science advances},
volume = {11},
number = {48},
pages = {eadw8410},
doi = {10.1126/sciadv.adw8410},
pmid = {41313780},
issn = {2375-2548},
mesh = {*Alzheimer Disease/metabolism/drug therapy ; *Gastrointestinal Microbiome ; Animals ; Humans ; *Indoles/metabolism/pharmacology ; *Cognition/drug effects ; Mice ; Mice, Transgenic ; Male ; Amyloid beta-Peptides/metabolism ; Disease Models, Animal ; Hippocampus/metabolism ; *Propionates/metabolism/pharmacology ; Cognitive Dysfunction ; Female ; },
abstract = {Intermittent fasting (IF) offers a potential strategy to counteract Alzheimer's disease (AD) progression. In our 16-week study on AD transgenic mice, IF positively affected cognitive function and reduced amyloid-β (Aβ) accumulation, verifying the IF's role in modulating neuroinflammation. Multiomics integration revealed strong links between IF-induced hippocampal gene expression, gut microbiota, and serum metabolites beneficial for cognition. Indole-3-propionic acid (IPA) emerged as a pivotal microbial metabolite. Blocking its neuronal receptor, pregnane X receptor (PXR), abolished IF's effects. Human data paralleled these findings, showing lower IPA levels in patients with mild cognitive impairment and AD than in controls. IPA supplementation and IPA-producing Clostridium sporogenes reproduced IF's cognitive benefits, whereas PXR blockade in neurons or disruption of IPA synthesis abrogated them. IPA crossed the blood-brain barrier, exhibited potent anti-inflammatory activity, and suppressed Aβ accumulation, essential for neuroprotection. These results underscore microbial metabolites regulated by IF, particularly IPA, as therapeutic candidates for AD, highlighting the critical role of the gut-brain axis in neurodegeneration.},
}

*Alzheimer Disease/metabolism/drug therapy
*Gastrointestinal Microbiome
Animals
Humans
*Indoles/metabolism/pharmacology
*Cognition/drug effects
Mice
Mice, Transgenic
Male
Amyloid beta-Peptides/metabolism
Disease Models, Animal
Hippocampus/metabolism
*Propionates/metabolism/pharmacology
Cognitive Dysfunction
Female

@article {pmid41313764,
year = {2025},
author = {Ozdemir, RA and Passera, B and Fried, PJ and Press, D and Shaughnessy, LW and Buss, S and Shafi, MM},
title = {Neurophysiological signatures of default mode network dysfunction and cognitive decline in Alzheimer's disease.},
journal = {Science advances},
volume = {11},
number = {48},
pages = {eadt8991},
doi = {10.1126/sciadv.adt8991},
pmid = {41313764},
issn = {2375-2548},
mesh = {*Alzheimer Disease/physiopathology ; Humans ; *Cognitive Dysfunction/physiopathology ; Electroencephalography ; Male ; Female ; Transcranial Magnetic Stimulation ; Aged ; *Default Mode Network/physiopathology ; Brain/physiopathology ; *Nerve Net/physiopathology ; Magnetic Resonance Imaging ; },
abstract = {Neural hyperexcitability and network dysfunction are neurophysiological hallmarks of Alzheimer's disease (AD) in animal studies, but their presence and clinical relevance in humans remain poorly understood. We introduce a perturbation-based approach combining transcranial magnetic stimulation and electroencephalography (TMS-EEG), alongside resting-state EEG (rsEEG), to investigate neurophysiological basis of default mode network (DMN) dysfunction in early AD. While rsEEG revealed global neural slowing and disrupted synchrony, these measures reflected widespread changes in brain neurophysiology without network-specific insights. In contrast, TMS-EEG identified network-specific local hyperexcitability in the parietal DMN and disrupted connectivity with frontal DMN regions, which uniquely predicted distinct cognitive impairments and mediated the link between structural brain integrity and cognition. Our findings provide critical insights into how network-specific neurophysiological disruptions contribute to AD-related cognitive dysfunction. Perturbation-based assessments hold promise as potential markers of early detection, disease progression, and target engagement for disease-modifying therapies aiming to restore abnormal neurophysiology in AD.},
}

*Alzheimer Disease/physiopathology
Humans
*Cognitive Dysfunction/physiopathology
Electroencephalography
Male
Female
Transcranial Magnetic Stimulation
Aged
*Default Mode Network/physiopathology
Brain/physiopathology
*Nerve Net/physiopathology
Magnetic Resonance Imaging

@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 {pmid41313603,
year = {2025},
author = {Mottaqi, M and Zhang, P and Xie, L},
title = {Integrating explainable artificial intelligence with multiomics systems biology and electronic health record data mining for personalized drug repurposing in Alzheimer's disease.},
journal = {Briefings in bioinformatics},
volume = {26},
number = {6},
pages = {},
doi = {10.1093/bib/bbaf623},
pmid = {41313603},
issn = {1477-4054},
support = {R01GM122845//National Institute of General Medical Sciences of the National Institute of Health/ ; R01AG057555//National Institute on Aging of the National Institute of Health/ ; R21AG083302//National Institute on Aging of the National Institute of Health/ ; 2226183//National Science Foundation/ ; },
mesh = {*Alzheimer Disease/drug therapy/genetics/metabolism ; Humans ; *Drug Repositioning/methods ; *Electronic Health Records ; *Data Mining/methods ; *Precision Medicine ; *Systems Biology/methods ; *Artificial Intelligence ; Gene Regulatory Networks ; Multiomics ; },
abstract = {Alzheimer's disease (AD) is characterized by region- and patient-specific molecular heterogeneity, which hinders therapeutic design. In this study, we introduce PRISM-ML (PRecision-medicine using Interpretable Systems and Multiomics with Machine Learning), an open-source integrated analysis pipeline that combines interpretable machine learning with systems biology and electronic health records data mining to elucidate the molecular diversity of AD and predict promising drug repurposing opportunities. First, we integrated and harmonized transcriptomic (bulk RNA-seq) and genomic (genome-wide association study) data from 2105 brain samples, each with matched data from the same individual (1363 AD patients, 742 controls; 9 tissues), sourced from three independent studies. Random forest classifiers with SHapley Additive exPlanations identified patient-specific biomarkers; unsupervised clustering resolved 36 molecularly distinct subtissues (defined as clusters of samples within a brain tissue that share a specific expression pattern); and gene-gene coexpression networks prioritized 262 high-centrality bottleneck genes as putative regulators of dysregulated pathways. Next, knowledge graph-based drug repurposing predicted six Food and Drug Administration (FDA)-approved drugs that simultaneously target multiple bottleneck genes and multiple AD-relevant pathways. Notably, in a large US de-identified insurance-claims database (n = 364 733), exposure to promethazine, one of the candidate drugs, was associated with a 57%-62% lower incidence of AD versus an active antihistamine comparator (adjusted hazard ratio 0.38; inverse-probability weighted 0.43; both P < .001), providing real-world support for its repurposing potential. In summary, PRISM-ML, as an explainable multiomics analysis pipeline, is readily transferable to other complex diseases, advancing precision medicine.},
}

*Alzheimer Disease/drug therapy/genetics/metabolism
Humans
*Drug Repositioning/methods
*Electronic Health Records
*Data Mining/methods
*Precision Medicine
*Systems Biology/methods
*Artificial Intelligence
Gene Regulatory Networks
Multiomics

@article {pmid41313529,
year = {2025},
author = {Li, X and Guo, Z and Li, Q and Li, C and Zhang, X},
title = {Potential Mechanisms of Exercise-Mediated Ferroptosis Regulation in Central Nervous System Diseases.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {198},
pmid = {41313529},
issn = {1559-1182},
mesh = {Humans ; *Ferroptosis/physiology ; *Exercise/physiology ; Animals ; *Central Nervous System Diseases/metabolism/pathology/therapy/physiopathology ; },
abstract = {As a common health-promoting intervention, exercise is widely recommended for patients with central nervous system (CNS) disorders such as stroke, Parkinson's disease (PD), and Alzheimer's disease (AD). In current clinical practice, however, exercise intensity is often determined based on therapist experience, with low-to-moderate intensities typically chosen for safety reasons. Thus, clarifying the underlying mechanisms is essential for developing precise and personalized exercise prescriptions in the future. Evidence shows that exercise regulates various "exerkines" (e.g., BDNF, Nrf2, TNFAIP3, and SLC2A1), which promote neural repair and influence iron metabolism. Ferroptosis-an iron-dependent, programmed cell death distinct from apoptosis, necrosis, and autophagy-is closely associated with the progression and prognosis of many diseases, particularly those affecting the CNS. This review synthesizes current understanding of ferroptosis in stroke, PD, and AD, describes how key exercise parameters (intensity, type-aerobic vs. resistance, and duration) influence ferroptosis, and summarizes preclinical and clinical evidence on exercise-induced ferroptosis modulation in CNS disorders. Our aim is to provide a mechanistic basis for optimizing exercise prescriptions to enhance functional recovery in patients with CNS conditions.},
}

Humans
*Ferroptosis/physiology
*Exercise/physiology
Animals
*Central Nervous System Diseases/metabolism/pathology/therapy/physiopathology

@article {pmid41313510,
year = {2025},
author = {Ciric, J and Perovic, M and Milovanovic, N and Polaka, S and Jovanovic Macura, I and Nestorovic, N and Tesic, V},
title = {Every-Other-Day Feeding Prevents the Loss of Parvalbumin-Expressing Neurons in the Cerebral Cortex of Female 5xFAD Mice.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {195},
pmid = {41313510},
issn = {1559-1182},
support = {451-03-136/2025-03/200007//Ministry of Science, Technological Development and Innovation of the Republic of Serbia/ ; 24IVPHA1288043//American Heart Association/ ; 23CDA1051814//American Heart Association/ ; },
mesh = {Animals ; *Parvalbumins/metabolism ; Female ; Mice, Transgenic ; *Cerebral Cortex/pathology/metabolism ; Brain-Derived Neurotrophic Factor/metabolism ; Alzheimer Disease/pathology/metabolism ; *Neurons/metabolism/pathology ; Interneurons/metabolism/pathology ; Mice ; Receptor, trkB/metabolism ; Amyloid beta-Peptides/metabolism ; *Feeding Behavior ; },
abstract = {The present study demonstrates the effects of an every-other-day (EOD) feeding regimen on parvalbumin (PV)-expressing interneurons in the cortex of 5xFAD mice, a well-established animal model of Alzheimer's disease (AD). Female 5xFAD mice and their non-transgenic littermates were maintained on either an ad libitum (AL) or EOD feeding regimen throughout the presymptomatic phase of the pathology, with comprehensive immunohistochemical and Western blot analyses performed in 6-month-old animals. In AL-fed 5xFAD mice, significant reductions in PV-expressing interneurons were observed in the retrosplenial granular, parietal, and somatosensory cortices compared to non-transgenic controls, supporting their established vulnerability in AD pathology. This neuronal loss was accompanied by a decline in the levels of brain-derived neurotrophic factor (BDNF), a key neurotrophin essential for cell survival and synaptic plasticity. Remarkably, four months of EOD feeding prevented the Aβ-induced loss of PV interneurons and increased the total protein levels of the BDNF receptor TrkB, suggesting enhanced neurotrophic signaling. However, the benefits of EOD feeding were not uniform across all molecular markers, with EOD-fed 5xFAD mice retaining deficits in phosphorylated CaMKII and CREB-binding protein (CBP) and biochemical analysis of plasma indicating metabolic stress-related effects. Together, these results align with the GABAergic hypofunction hypothesis in AD, underscoring the importance of PV interneuron plasticity in neurodegeneration and cognitive decline. They also suggest that dietary strategies like EOD feeding may offer partial neuroprotective effects during early AD progression, however, complex stress-related impacts of EOD in the modulation of PV neuron function remain to be elucidated. Future studies are also warranted to more carefully explore the long-term translational potential of dietary interventions and the interplay between metabolic stress and amyloid pathology, in order to identify novel therapeutic targets across distinct neuronal populations.},
}

Animals
*Parvalbumins/metabolism
Female
Mice, Transgenic
*Cerebral Cortex/pathology/metabolism
Brain-Derived Neurotrophic Factor/metabolism
Alzheimer Disease/pathology/metabolism
*Neurons/metabolism/pathology
Interneurons/metabolism/pathology
Mice
Receptor, trkB/metabolism
Amyloid beta-Peptides/metabolism
*Feeding Behavior

@article {pmid41313418,
year = {2025},
author = {Xue, H and Bi, S and Chen, Z and He, Y and Xu, W and Xu, X and Cui, B and Hu, Y and Qi, Z and Yan, S and Lu, J},
title = {Glymphatic system dysfunction mediates amyloid deposition and cognitive impairment in Alzheimer's disease: a PET/MRI multimodality imaging study.},
journal = {EJNMMI research},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13550-025-01339-y},
pmid = {41313418},
issn = {2191-219X},
support = {82394434//National Natural Science Foundation of China/ ; 82102010//National Natural Science Foundation of China/ ; },
}

@article {pmid41313410,
year = {2025},
author = {Goel, F and Singh, P and Rai, SN and Yadav, DK},
title = {Nrf2/Keap1 Signaling Axis in the Brain: Master Regulator of Oxidative Stress in Neurodegenerative and Psychiatric Disorders.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {197},
pmid = {41313410},
issn = {1559-1182},
mesh = {Humans ; *Kelch-Like ECH-Associated Protein 1/metabolism ; *NF-E2-Related Factor 2/metabolism ; *Signal Transduction/physiology ; *Oxidative Stress/physiology ; *Mental Disorders/metabolism/pathology ; Animals ; *Neurodegenerative Diseases/metabolism/pathology ; *Brain/metabolism/pathology ; },
abstract = {Oxidative stress is a crucial factor in the development of CNS disorders, including neurodegenerative and psychiatric conditions. The Nrf2/Keap1 signaling axis plays a central role in defending against oxidative damage by regulating antioxidant and cytoprotective gene expression. Beyond its antioxidant function, Nrf2 influences neurogenesis, synaptic plasticity, mitochondrial bioenergetics, and glial neuronal interactions, all of which are vital for maintaining neural integrity and cognitive performance. Dysregulation of this pathway through altered dimerization, post-translational modifications, or impaired regulation contributes to the pathophysiology of Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis, leading to protein aggregation, mitochondrial dysfunction, and neuroinflammation. Emerging evidence also implicates aberrant Nrf2 activity in psychiatric disorders such as depression, schizophrenia, and bipolar disorder, where redox imbalance and neuroimmune activation disrupt neural function. This review summarizes the molecular structure and regulation of the Nrf2/Keap1 pathway, including basal and stress-induced activation, post-translational modifications, and cross-talk with PI3K/Akt, MAPK, and NF-κB signaling. We highlight cell-type-specific roles of Nrf2 in neurons, astrocytes, and microglia, and the gene expression networks that drive CNS antioxidant and detoxification responses. Recent therapeutic strategies include natural and synthetic Nrf2 activators, gene therapy approaches, and nanotechnology-based delivery systems. While the translational potential of Nrf2-targeted interventions is considerable, challenges remain, including risks of overactivation and oncogenicity, lack of reliable biomarkers, and barriers related to blood-brain barrier permeability, dose, timing, and bioavailability. By integrating advances in neuroscience, pharmacology, and molecular medicine, this review emphasizes the promise of Nrf2 as a unifying therapeutic target across diverse CNS pathologies. Future directions include precision modulation through epigenetic regulation and circRNAs, as well as personalized pharmacotherapy. The Nrf2/Keap1 axis represents a multidisciplinary platform for developing multimodal interventions to preserve brain health in neurodegenerative and psychiatric disorders.},
}

Humans
*Kelch-Like ECH-Associated Protein 1/metabolism
*NF-E2-Related Factor 2/metabolism
*Signal Transduction/physiology
*Oxidative Stress/physiology
*Mental Disorders/metabolism/pathology
Animals
*Neurodegenerative Diseases/metabolism/pathology
*Brain/metabolism/pathology

@article {pmid41313318,
year = {2025},
author = {Ai, R and Fang, EF},
title = {NAD+ restores proteostasis through splicing-dependent autophagy.},
journal = {Autophagy},
volume = {},
number = {},
pages = {},
doi = {10.1080/15548627.2025.2596679},
pmid = {41313318},
issn = {1554-8635},
abstract = {Autophagy preserves neuronal integrity by clearing damaged proteins and organelles, but its efficiency declines with aging and neurodegeneration. Depletion of the oxidized form of nicotinamide adenine dinucleotide (NAD[+]) is a hallmark of this decline, yet how metabolic restoration enhances autophagic control has remained obscure. Meanwhile, alternative RNA splicing errors accumulate in aging brains, compromising proteostasis. Here, we identify a metabolic - transcriptional mechanism linking NAD[+] metabolism to autophagic proteostasis through the NAD[+] -EVA1C axis. Cross-species analyses in C. elegans, mice, and human samples reveal that NAD[+] supplementation corrects hundreds of age- or Alzheimer-associated splicing errors, notably restoring balanced expression of EVA1C isoforms. Loss of EVA1C impairs the memory and proteostatic benefits of NAD[+], underscoring its essential role in neuronal resilience. Mechanistically, NAD[+] rebalances EVA1C isoforms that interact with chaperones BAG1 and HSPA/HSP70, reinforcing their network to facilitate chaperone-assisted selective autophagy and proteasomal degradation of misfolded proteins such as MAPT/tau. Thus, NAD[+] restoration coordinates RNA splicing fidelity with downstream proteostatic systems, establishing a metabolic - transcriptional checkpoint for neuronal quality control. This finding expands the paradigm of autophagy regulation, positioning metabolic splice-switching as a crucial mechanism to maintain proteostasis and suggesting new strategies to combat aging-related neurodegenerative diseases.},
}

@article {pmid41313317,
year = {2025},
author = {Iwasa, K and Takamura, M and Ishida, M and Kuroda, Y and Abe, S and Nagai, A},
title = {Cognitive test completion time as an indicator of early brain atrophy: Findings from the Cognitive Assessment for Dementia, iPad version 2 (CADi2) in healthy adults.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251400746},
doi = {10.1177/13872877251400746},
pmid = {41313317},
issn = {1875-8908},
abstract = {BackgroundAlthough several cognitive screening tools are available, early-stage detection remains challenging because individuals in prodromal or mild cognitive impairment stages often score within normal ranges. Assessment of response time, rather than test score alone, may offer greater sensitivity to subtle decline.ObjectiveTo examine whether completion time on the Cognitive Assessment for Dementia, iPad version 2 (CADi2), is associated with early brain changes suggestive of preclinical dementia.MethodsIn this cross-sectional study of 511 cognitively unimpaired adults (290 men, 221 women; mean age, 61 years) at the Health Science Center, Japan, participants completed the 10-item CADi2 and underwent structural magnetic resonance imaging. Based on the ceiling effects in total scores, we analyzed associations between total test duration and regional brain atrophy.ResultsCADi2 time was significantly associated with hippocampal atrophy, while total scores were not. We applied a deep survival analysis model using Alzheimer's Disease Neuroimaging Initiative data to estimate 5-year dementia risk. Using a threshold of ≥0.25, receiver operating characteristic analysis showed that CADi2 time (area under the curve, 0.632) outperformed CADi2 (0.554) and Mini-Mental State Examination (0.582) scores. Only CADi2 time showed a significant odds ratio [OR] for high dementia risk (OR = 1.94; 95% confidence interval: 1.12-3.40; p = 0.018) after adjusting for covariates.ConclusionsThese findings indicate that completion time from a cognitive test without ceiling effects is more suitable than score-based measures for evaluating the predementia stage and that combining time and score metrics may further improve stratification in cognitively normal individuals.},
}

@article {pmid41313305,
year = {2025},
author = {Álvarez-Pérez, Y and Duarte-Díaz, A and Molina, Y and Figueroa-Lamas, N and Diaz-Galvan, P and García-Cabello, E and Gonzalez-Burgos, L and Yánes-Pérez, R and Rivero-Santana, A and Olofsson, JK and Barroso, J and Ferreira, D and Perestelo-Pérez, L and Cedres, N},
title = {Underexplored moderating effects of sex in subjective cognitive decline: A systematic review and evidence gap.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251397411},
doi = {10.1177/13872877251397411},
pmid = {41313305},
issn = {1875-8908},
abstract = {BackgroundSubjective cognitive decline (SCD) is considered an early symptom of Alzheimer's disease (AD) and other types of dementia. Establishing differences between males and females in the presentation and risk factors associated with SCD is critical for utilizing subjective cognitive assessments in prognosticating dementia.ObjectiveWe performed a comprehensive review of studies examining the moderating effect of sex on the association between SCD and relevant physical and/or mental health-related outcomes.MethodsThis study was performed following the PRISMA guidelines. We conducted database search in Medline, Cochrane, Web of Science (WOS), and CINAHL. Primary studies including data of the moderating effect of sex on the association between SCD and different outcomes were selected.ResultsA total of 16 studies were included. We found limited evidence for a moderating effect of sex in SCD. Most of the available literature explored sex differences in SCD for risk of dementia, cognitive performance, competing risk of death, AD biomarkers, basal forebrain resting-state functional connectivity, brain volume, among other health outcomes. Among SCD individuals, females showed increased risk of cognitive decline, dementia and other health outcomes, whereas males showed increased risk of death and longer sickness absence compared to controls.ConclusionsOur comprehensive review denotes a lack of studies directly testing the moderating effect of sex in SCD. The available literature points to sex specific associations between SCD and multiple clinical outcomes. However, in line with the current effort of the SCD initiative, further research is necessary within this emerging topic.},
}

@article {pmid41313166,
year = {2025},
author = {Hayes, KN and Belanger, E and Oganisian, A and Joshi, R and Wang, XJ and Grove, LR and Corcoran, KL and Zullo, AR},
title = {Predictors of a Gabapentinoid-Loop-Diuretic Prescribing Cascade in U.S. Nursing Home Residents.},
journal = {Journal of the American Geriatrics Society},
volume = {},
number = {},
pages = {},
doi = {10.1111/jgs.70219},
pmid = {41313166},
issn = {1532-5415},
support = {RF1AG089541/AG/NIA NIH HHS/United States ; },
abstract = {BACKGROUND: Gabapentinoid-related peripheral edema may prompt loop diuretic prescribing. Nursing home (NH) residents may be especially prone to this prescribing cascade. We estimated the incidence and identified predictors of the gabapentinoid-loop diuretic prescribing cascade in NHs.

METHODS: We conducted a retrospective cohort study using 2016-2022 Medicare claims linked with Minimum Data Set assessments. We identified residents aged ≥ 66 years who initiated gabapentinoids in NHs and who had no evidence of loop diuretic use, heart failure, or renal insufficiency during the prior 6 months. The outcome was loop diuretic initiation within 90 days of gabapentinoid initiation. Using multivariable Poisson regression models, we estimated adjusted risk ratios (aRR) with 95% robust confidence intervals to identify predictors. We used pooled logistic regression models to examine the relationship between time-varying gabapentinoid dose and loop diuretic initiation risk.

RESULTS: Among 23,544 residents, 994 (4.2%) experienced a prescribing cascade at a median of 36 days (IQR 15-61) after gabapentinoid initiation. Risk was higher with age 86-90 years (aRR = 1.60) or ≥ 91 years (aRR = 1.38); a diagnosis of chronic pain or fibromyalgia (aRR = 1.16), or diabetes (aRR = 1.23); and receipt of potassium-sparing diuretics (aRR = 1.53), thiazide diuretics (aRR = 1.27), or 15 or more unique medications (aRR = 1.18). Higher (versus lower) weekly gabapentin dose during follow-up was associated with a 1.45 times higher prescribing cascade risk over 13 weeks. Those with Alzheimer's Disease and Related Dementias (aRR = 0.79), or moderate (aRR = 0.72) to severe cognitive impairment (aRR = 0.59) had a lower risk versus those with intact cognition.

CONCLUSIONS: Approximately 1 in 20 NH residents who initiate gabapentinoids receives a loop diuretic within 3 months. Potentially modifiable predictors included existing polypharmacy and titrating gabapentinoid doses. NH clinicians should monitor for edema soon after gabapentinoid initiation and consider dose reductions or discontinuation before adding a loop diuretic.},
}

@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 {pmid41312650,
year = {2025},
author = {Marinho Barbosa, B and Esmieu, C and Galvácsi, A and Costa, MV and Brison, A and Ladeira, SM and de Oliveira, J and Kállay, C and Hureau, C and Rey, NA},
title = {Evaluation of a New Methylimidazole-Containing Thiosemicarbazone as a Cu[+]/Cu[2+]-Targeting Ligand in the Context of Alzheimer's Disease.},
journal = {Chemistry (Weinheim an der Bergstrasse, Germany)},
volume = {},
number = {},
pages = {e02754},
doi = {10.1002/chem.202502754},
pmid = {41312650},
issn = {1521-3765},
support = {ANR-20-CE07-0009//ANR project Copperation/ ; //Conselho Nacional de Desenvolvimento Científico e Tecnológico, Brazil/ ; //Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro/ ; 24/2551-0001978-2//Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul/ ; 88881.878977/2023-01//Coordenação de Aperfeiçoamento de Pessoal de Nível Superior/ ; },
abstract = {The binding of copper ions to amyloid-β (Aβ) peptide leads to reactive oxygen species (ROS) formation and toxic soluble oligomers, contributing to oxidative stress in Alzheimer's disease (AD). Thus, studying compounds with moderate copper affinity is a promising strategy to prevent its interaction with Aβ and reduce toxicity. Here, we evaluated a new tri-coordinating thiosemicarbazone (HXE) with chelating properties to regulate cuprotoxicity in AD. The ligand was nontoxic against HT-22 hippocampal neuronal cells and bound Cu[+] and Cu[2+] at pH 7.4, with affinity constants (log Kcond) of 8.7 and 12.3, respectively, showing high selectivity over Zn[2+] (log Kapp = 5.0). In the presence of Aβ and Cu[2+], HXE formed stable ternary complexes at physiological pH. Ascorbate consumption and coumarin-3-carboxylic acid fluorescence assays showed that the ligand significantly reduces Cu(Aβ16)-mediated ROS production. It also prevented Cu[2+]-induced modulation of Aβ40 self-assembly and restored the typical fibrillar structure of apo-Aβ40 aggregates. Overall, HXE effectively modulates metal-associated Aβ toxicity and emerges as a promising candidate for AD bioinorganic management.},
}

@article {pmid41312570,
year = {2025},
author = {Sonar, Y and Mahajan, D and Kole, E and Daude, R and Naik, J and Bhairav, B},
title = {Intranasal thermosensitive gel for brain-targeted delivery of α-Cyperone-loaded solid lipid nanoparticles.},
journal = {Therapeutic delivery},
volume = {},
number = {},
pages = {1-14},
doi = {10.1080/20415990.2025.2594295},
pmid = {41312570},
issn = {2041-6008},
abstract = {AIMS: To develop and evaluate α-Cyperone (α-Cy)-loaded solid lipid nanoparticles (SLNs) incorporated into a thermosensitive in situ gel for enhanced intranasal delivery and improved neuroprotective efficacy.

MATERIALS AND METHODS: α-Cy-SLN was prepared using high-pressure homogenization followed by freeze-drying. The formulation was optimized using a Box-Behnken Design, assessing the effects of lipid-to-surfactant ratio on particle size, polydispersity index (PDI), zeta potential, and entrapment efficiency (EE). The optimized SLNs were characterized for physicochemical properties, in vitro drug release, and brain cell penetration.

RESULTS: The optimized α-Cy-SLNs (Run 5) exhibited a mean particle size of 279.5 ± 0.06 nm, PDI of 0.203 ± 0.24, zeta potential of -23.1 ± 2.38 mV, EE of 70.0 ± 2.21%, and product yield of 72.58 ± 1.24%. In vitro studies demonstrated a sustained release of α-Cy from the SLNs, indicating the formulation's potential for prolonged drug delivery. Incorporation into the thermosensitive in situ gel further supported controlled release and enhanced bioavailability.

CONCLUSIONS: The developed α-Cy-SLN in situ gel formulation offers a promising strategy for intranasal delivery, improving α-Cy bioavailability and therapeutic potential for neuroprotection in Alzheimer's disease.},
}

@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 {pmid41312257,
year = {2025},
author = {Chaurasiya, M and Prasad, G},
title = {Identification of Ageing-related Hub Genes in Humans, Mouse and Rat Based on Bioinformatics Analysis.},
journal = {Annals of neurosciences},
volume = {},
number = {},
pages = {09727531251381065},
pmid = {41312257},
issn = {0972-7531},
abstract = {BACKGROUND: Ageing is a natural process observed in all living organisms. It is a complex biological process involving many genes and pathways. As such, ageing in an organism is associated with an increased likelihood of developing various neurological diseases, for example, Alzheimer's disease (AD) and Parkinson's disease (PD).

PURPOSE: Ageing is associated with many complex processes and functions that are highly interconnected. In this study, we identified pivotal nodes or hubs that significantly contribute to an ageing network, including those highly connected nodes within the network that are particularly important, using available bioinformatics tools in humans and other model organisms. Thus, mutating or altering any of these nodes in a network can result in significant changes in the overall functioning of an organism.

METHODS: For this study, the ageing genes of humans and mice were retrieved from the GenAge database, while the ageing genes of rats were retrieved from the Ageing & Age related Diseases present in Rat Genome Database. STRING (version 11.5), an online tool, was used to create the network. Cytoscape (version 3.10.0), an open-source software with an integrated tool called cytoHubba, was used to identify the hubs from the STRING network in humans, mice and rats. The online tool Enrichr was used to test the functional enrichment of hub genes in humans.

RESULTS: TP53, Trp53 and Actb were identified as important genes in the network, contributing significantly to the process of ageing in humans, mice and rats, respectively, along with others in the network.

CONCLUSION: Identification of these hubs from the network of ageing and ageing-associated genes deserves further investigation to advance existing knowledge and to improve our understanding of ageing in humans and other model organisms.},
}

@article {pmid41311763,
year = {2025},
author = {Inoue, T and Sawamura, S and Nagai, T and Kohiyama, K and Takenaka, T and Sera, T and Senba, L},
title = {Using AI-Based Gait Analysis to Establish a 5-Meter Walk Time Cutoff for Discriminating Alzheimer's Disease.},
journal = {Cureus},
volume = {17},
number = {10},
pages = {e95491},
pmid = {41311763},
issn = {2168-8184},
abstract = {Introduction A decline in gait function has been reported to occur early in Alzheimer's disease (AD), a major cause of dementia, suggesting that gait analysis may be a useful tool for dementia screening. However, a simple and practical analysis method or clear cutoff values have yet to be established. This study aimed to analyze gait function using the AI-powered smartphone application "Toruto," identify gait indicators characteristic of elderly patients with AD, and propose effective cutoff values for dementia discrimination. Methods A total of 147 participants were included in the study: 86 healthy elderly individuals and 61 elderly patients with AD (102 female patients and 45 male patients). Exclusion criteria included the use of a cane, the presence of pain during walking, or the need for walking assistance. Gait function at a normal walking speed was analyzed by the AI of "Toruto" to assess speed, rhythm, and left-right asymmetry. An unpaired t-test was used to compare the two groups, and cutoff values for dementia discrimination were calculated using receiver operating characteristic (ROC) curve analysis. The significance level was set at p < 0.05. Results The AD group showed a significant decline in gait speed (12.12 versus 3.98 sec/5 m), rhythm (10.92 versus 6.51), and left-right asymmetry (6.34 versus 2.15) compared with the healthy control group (p < 0.05). ROC curve analysis revealed that using a gait speed cutoff value of 5.85 sec/5 m yielded a sensitivity of 96.7% and a specificity of 96.5%. A rhythm cutoff of 7.06 (sensitivity: 80.3%, specificity: 65.1%) and a left-right asymmetry cutoff of 2.25 (sensitivity: 75.4%, specificity: 67.4%) were also effective discriminative indicators. Conclusion Gait analysis using the AI-powered smartphone application "Toruto" is effective for distinguishing Alzheimer's disease. This study demonstrated that cutoff values, such as 5.85 seconds for a 5-meter walk, serve as practical screening indicators for dementia. As an objective biomarker reflecting cognitive decline, gait function is expected to be useful for the early detection of Alzheimer's disease in both community and clinical settings.},
}

@article {pmid41311655,
year = {2025},
author = {Exarchos, TP and Dimakopoulos, GA and Lazaros, K and Krokidis, M and Vrahatis, A and Grammenos, G and Avramouli, A and Skolariki, K and Adams, R and Mahairaki, V and Oh, ES and Leoutsakos, J and Rosenberg, PB and Lyketsos, CG and Vlamos, P},
title = {Correction: Five-year dementia prediction and decision support system based on real-world data.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1719723},
doi = {10.3389/fnagi.2025.1719723},
pmid = {41311655},
issn = {1663-4365},
abstract = {[This corrects the article DOI: 10.3389/fnagi.2025.1670609.].},
}

@article {pmid41311654,
year = {2025},
author = {Montesinos, R and Olavarria, L and Henriquez, F and Chambergo-Michilot, D and Custodio, B and Delgado, C and Malaga, M and Custodio, N and Slachevsky, A},
title = {Diagnostic utility and psychometric properties of the Technology Activities of Daily Living Questionnaire (T-ADLQ) in people with non-formally educated with Alzheimer's disease in Lima, Peru.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1660345},
pmid = {41311654},
issn = {1663-4365},
abstract = {OBJECTIVE: To evaluate the discriminative capacity and psychometric properties of the Technology-Activities of Daily Living Questionnaire (T-ADLQ) in distinguishing cognitively unimpaired individuals from those with amnestic mild cognitive impairment (aMCI) and Alzheimer's disease dementia (ADD) in a population with no formal education.

METHODS: This cross-sectional study included individuals with no formal education over 50 years of age residing in Callao, Peru. Participants were classified into three cognitive groups: cognitively unimpaired (CU; n = 64), aMCI (n = 60), and early ADD (n = 63). Functional decline was assessed with the T-ADLQ. Group comparisons were conducted using the chi-square or ANOVA tests, as appropriate. Pearson correlations were used to assess concurrent validity. The reliability of the T-ADLQ was assessed using Cronbach's alpha. Receiver operating characteristic (ROC) curve analyses and area under the curve (AUC) metrics were used to assess the discriminative validity of the measures across the three cognitive groups.

RESULTS: In a sample of 187 illiterate older adults, the T-ADLQ demonstrated excellent internal consistency (Cronbach's α = 0.966) and strong inverse correlations with global and executive cognitive measures (MMSE, RUDAS, IFS). It also showed a moderate positive correlation with PFAQ. ROC analyses revealed excellent discriminative performance of the T-ADLQ. The total score and the instrumental (IADL) and advanced (AADL) domains achieved perfect accuracy in differentiating cognitively unimpaired individuals from those with aMCI or ADD. The basic activities of daily living (BADL) domain also showed high accuracy, particularly in distinguishing aMCI from ADD.

CONCLUSION: The T-ADLQ and its subdomains exhibit strong psychometric properties and high discriminative capacity in detecting functional decline in individuals with aMCI and ADD. These findings support the T-ADLQ as a valid and reliable tool for assessing functional impairment in populations with no formal education.},
}

@article {pmid41311528,
year = {2025},
author = {Roy, ER and Cao, W},
title = {Advancing Alzheimer's research by improving disease modeling of secondary tauopathy.},
journal = {NPJ dementia},
volume = {1},
number = {1},
pages = {38},
pmid = {41311528},
issn = {3005-1940},
abstract = {Despite decades of mechanistic investigation of Alzheimer's disease (AD), wide gaps exist in disease modeling, particularly the pathobiological arm of tau pathology. Relying on transgenic models expressing mutated forms of tau has contributed much knowledge about primary tauopathy, yet with limited relevance to human AD. To eliminate blind spots for basic and translational research, we review recent developments in this area and discuss key refinements toward next-generation AD-relevant tauopathy modeling.},
}

@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 {pmid41311354,
year = {2025},
author = {Baun, AM and Firbank, M and Hinz, R and Terkelsen, MH and Iranzo, A and Gaig, C and Tolosa, E and Brooks, DJ and Pavese, N and Keogh, M},
title = {[[11]C](R)-PK11195 Positron Emission Tomography Imaging of Skull Inflammation in Isolated Rapid-Eye-Movement Sleep Behavior Disorder.},
journal = {Movement disorders : official journal of the Movement Disorder Society},
volume = {},
number = {},
pages = {},
doi = {10.1002/mds.70133},
pmid = {41311354},
issn = {1531-8257},
support = {CB06/05/0018//Instituto de Salud Carlos III/ ; R4-A104-B60//Danish Parkinson's Association/ ; 4004-00480B//Danmarks Frie Forskningsfond/ ; 8020-00260B//Danmarks Frie Forskningsfond/ ; },
abstract = {BACKGROUND: Skull bone marrow is a specialized immune compartment supplying cells to the meninges. Experimental evidence suggests skull marrow activity may contribute to neuroinflammation in early Parkinson's disease, but in vivo assessment has not yet been performed in any α-synucleinopathy.

OBJECTIVE: The objective is to assess skull/meningeal inflammatory activity in patients with isolated rapid-eye-movement sleep behavior disorder (iRBD).

METHODS: 20 iRBD patients recieved longitudinal [[11]C](R)-PK11195 positron emission tomography scans and were compared to 19 healthy controls.

RESULTS: Global skull inflammation in the iRBD patients was 22.87% higher (95% confidence interval: 12.78-32.97) compared to controls, especially in frontal regions, differing from that previously reported in Alzheimer's disease and multiple sclerosis. This inflammation progressed during a 3-year follow-up period but did not correlate with phenoconversion.

CONCLUSION: This is the first in vivo evidence of skull marrow activation in an α-synucleinopathy. Our findings support a role for the skull-meningeal immune axis in iRBD, linking peripheral and central inflammation in prodromal disease. © 2025 International Parkinson and Movement Disorder Society.},
}

@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 {pmid41310967,
year = {2025},
author = {Tschirner, SK and Schmidt, A and Ito, M and Hyakkoku, K and Yoshimura, A and Müller, SA and Horiguchi, N and Lichtenthaler, SF},
title = {Elenbecestat and Compound 89 Potently Inhibit BACE1 but Not BACE2 When Subchronically Dosed in Non-Human Primates.},
journal = {Proteomics},
volume = {},
number = {},
pages = {e70082},
doi = {10.1002/pmic.70082},
pmid = {41310967},
issn = {1615-9861},
support = {EXC 2145 SyNergy-ID 390857198//Deutsche Forschungsgemeinschaft (DFG, German Research Foundation)/ ; FKZ03LW0246//Federal Ministry of Research, Technology, and Space/ ; SG-23-1029755 BACE/ALZ/Alzheimer's Association/United States ; },
abstract = {The β-secretase BACE1 (β-site amyloid precursor (APP) cleaving enzyme 1) is a major drug target for Alzheimer's disease (AD), as it catalyzes the first step in amyloid β (Aβ) generation, but has additional substrates and functions, in particular in the brain. Several advanced clinical trials with BACE1 inhibitors were stopped because of an adverse event, a mild cognitive worsening. The underlying mechanism is not yet known but may result from co-inhibition of the BACE1-homolog BACE2. While a cerebrospinal fluid (CSF) biomarker for measuring BACE2 activity is not yet established, VCAM-1 has been suggested as such a biomarker, but has not yet been tested upon prolonged dosing in vivo. Using CSF pharmacoproteomics and a subchronic dosing paradigm in non-human primates, we demonstrate that compound 89, a BACE inhibitor not yet tested in humans, and the clinically tested drug elenbecestat inhibit BACE1 in vivo, with little or no effect on BACE2, as seen with a reduction of substrates of BACE1, but not of the BACE2 substrate VCAM-1. As a control, verubecestat, which inhibits both BACE2 and BACE1, reduced CSF abundance of BACE1 substrates as well as of VCAM-1. This study demonstrates the suitability of VCAM-1 as a pharmacodynamic biomarker for measuring BACE2 target engagement in CSF.},
}

@article {pmid41310918,
year = {2025},
author = {Pinnamaneni, A and Akkiraju, A and Park, HI and Ch V, RSR and Ayalasomayajula, V and Bandela, M and Kaipa, S and Khosla, S and Zeineh, M and Suryadevara, V and , },
title = {Beyond Structure: The Interplay of Bone and Brain During Alzheimer's Disease.},
journal = {Comprehensive Physiology},
volume = {15},
number = {6},
pages = {e70075},
doi = {10.1002/cph4.70075},
pmid = {41310918},
issn = {2040-4603},
support = {W81XWH-12-2-0012//U.S. Department of Defense/ ; ADNI U01 AG024904/NH/NIH HHS/United States ; },
mesh = {*Alzheimer Disease/metabolism/pathology/physiopathology ; Humans ; Animals ; *Brain/metabolism/pathology ; *Bone and Bones/metabolism/pathology ; Bone Remodeling ; },
abstract = {Alzheimer's disease (AD), a leading cause of dementia in the elderly, is traditionally characterized by neurodegeneration driven by amyloid-beta plaques and tau tangles. However, emerging evidence reveals that AD's impact extends beyond the brain, significantly affecting skeletal health. This review integrates clinical and transgenic mouse model data to elucidate the mechanistic interplay between AD pathology and bone metabolism. AD patients exhibit increased risk for hip fractures and low bone mineral density (BMD), independent of cognitive impairment severity. We found altered calcium and alkaline phosphate levels in the blood of patients with mild cognitive impairment and AD, as assessed from the Alzheimer's Disease Neuroimaging Initiative data. Convergent risk factors-age, sex, APOE4 genotype, smoking, and vitamin D deficiency-contribute to both neurodegeneration and bone fragility. Key molecular pathways, such as Wnt/β-catenin signaling and TREM2-mediated osteoclast regulation, underscore shared mechanisms driving disease pathology in both systems. Mouse models of AD consistently demonstrate disrupted bone remodeling, impaired osteoblast function, and heightened osteoclast activity. Therapeutic strategies targeting overlapping pathways, including lithium, anti-FSH antibodies, and NF-κB inhibitors, show promise in mitigating both cognitive decline and bone loss. Collectively, these insights advocate for a more integrated view of AD that includes skeletal comorbidities, potentially guiding the development of dual-purpose interventions.},
}

*Alzheimer Disease/metabolism/pathology/physiopathology
Humans
Animals
*Brain/metabolism/pathology
*Bone and Bones/metabolism/pathology
Bone Remodeling

@article {pmid41310910,
year = {2025},
author = {Tsai, CH and Huang, SY and Lin, YN and Wang, HW and Hsiao, IT and Chen, KT},
title = {Paired PET-MRI Deep Learning Model for Translating [[11]C]PiB to [[18]F]Florbetaben Amyloid Images.},
journal = {Medical physics},
volume = {52},
number = {12},
pages = {e70168},
doi = {10.1002/mp.70168},
pmid = {41310910},
issn = {2473-4209},
support = {NTU-114L7872//Ministry of Education, Taiwan R.O.C./ ; NTU-114L900703//Ministry of Education, Taiwan R.O.C./ ; NTU-113V1015-4//Ministry of Education, Taiwan R.O.C./ ; NTU-114V1015-5//Ministry of Education, Taiwan R.O.C./ ; 114-2628-E-002-019-MY3//National Science and Technology Council/ ; NHRI-EX114- 11205EC//National Health Research Institutes/ ; },
mesh = {*Stilbenes ; *Aniline Compounds ; *Positron-Emission Tomography ; *Magnetic Resonance Imaging ; Humans ; *Deep Learning ; *Image Processing, Computer-Assisted/methods ; *Thiazoles ; *Benzothiazoles ; Carbon Radioisotopes ; *Multimodal Imaging ; *Amyloid/metabolism ; Alzheimer Disease/diagnostic imaging ; *Amyloid beta-Peptides/metabolism ; },
abstract = {BACKGROUND: Amyloid PET imaging has been extensively employed in the noninvasive assessment of amyloid-beta accumulation in Alzheimer's disease. Various amyloid radiotracers are commonly used in clinical settings; however, the limited interchangeability among these radiotracers hinders the feasibility of long-term clinical trials and multicenter comparisons. The Centiloid method was proposed for standardization, though providing a single score per image; voxel-wise translation remains a formidable task.

PURPOSE: This paper proposes a U-Net model based on a deformable convolution network (DCNv3-based U-Net) for [ 11 C $^{11}\
textrm {C}$
]-Pittsburgh compound B-to-[ 18 F $^{18}\
textrm {F}$
]-florbetaben image translation to augment existing datasets for large-scale model training and provide image information when inconsistencies between visual assessments and the Centiloid scale occur.

METHODS: The DCNv3-based U-Net combined the benefits of deformable convolution that captures long-range dependencies with efficient computation and the encoder-decoder architecture with skip connections for local-global feature learning and image synthesis.

RESULTS: The prediction images presented increased homogeneity to other previous models, closely resembling the texture of [ 18 F $^{18}\
textrm {F}$
]-florbetaben.

CONCLUSIONS: The DCNv3-based U-Net demonstrated high performance in metrics measurement and statistical analyses for the PET image-to-image translation task. This work also justified the importance of MR images in providing structural information.},
}

*Stilbenes
*Aniline Compounds
*Positron-Emission Tomography
*Magnetic Resonance Imaging
Humans
*Deep Learning
*Image Processing, Computer-Assisted/methods
*Thiazoles
*Benzothiazoles
Carbon Radioisotopes
*Multimodal Imaging
*Amyloid/metabolism
Alzheimer Disease/diagnostic imaging
*Amyloid beta-Peptides/metabolism

@article {pmid41310626,
year = {2025},
author = {Vega, MR and Hansen, HH and Jensen, CS and Alexiou, E and Madsen, MR and Wichern, F and Kristiansen, MS and Skytte, JL and Salinas, CG and Sotty, F and Jensen, A and Vergo, S and Hecksher-Sørensen, J},
title = {Transferrin receptor-binding blood-brain barrier shuttle enhances brain delivery and plaque-clearing efficacy of a therapeutic anti-Aβ antibody.},
journal = {Fluids and barriers of the CNS},
volume = {22},
number = {1},
pages = {121},
pmid = {41310626},
issn = {2045-8118},
}

@article {pmid41310442,
year = {2025},
author = {Giudicessi, A and Koops, E and Vila-Castelar, C and Martinez, L and Ramirez-Perez, N and Silva, G and Medrano, R and Martinez, JE and Solis, I and Alcina, J and Tristão-Pereira, C and Gonzalez Catalan, M and Saldana, DG and Ramírez-Gómez, L and Cronin-Golomb, A and Quiroz, YT},
title = {Association between reproductive history, white matter integrity, and cognition in post-menopausal Latina women from the Boston Latino Aging Study.},
journal = {Journal of clinical and experimental neuropsychology},
volume = {},
number = {},
pages = {1-15},
doi = {10.1080/13803395.2025.2591895},
pmid = {41310442},
issn = {1744-411X},
abstract = {BACKGROUND: Women face disproportionately high Alzheimer's disease (AD) rates, with Latina women experiencing particularly elevated cognitive impairment rates. Understanding reproductive factors' impact on brain aging is critical for this underrepresented population. Given sex disparities in AD and reproductive factor influence on brain aging, we examined relations among reproductive history, white matter integrity, and cognitive function in post-menopausal Latina women.

METHODS: Participants were 95 post-menopausal Latina women from the Boston Latino Aging Study, mean age 65.7 (SD = 6.5) years and 11.7 (SD = 4.8) years of education. Reproductive history was obtained via self-report questionnaire. Cognitive assessment included Mini-Mental State Examination, Free and Cued Selective Reminding Test, Category Fluency, Story Memory Delayed Recall, and Symbol Digit Modalities Test administered in Spanish or Portuguese. White matter microstructure was assessed with diffusion weighted imaging using fixel-based methods. Regression models tested associations among reproductive factors, cognitive and imaging outcomes, adjusting for age, education, and cardiovascular risk. Mediation analyses evaluated whether white matter abnormalities explained reproductive-cognitive relations.

RESULTS: Pregnancy history was associated with worse delayed recall, with women having 1-2 (β = -0.79, p = .016) and 3-4 term pregnancies (β = -0.93, p = .005) performing worse than nulliparous women. Overall, hormone replacement therapy use was associated with better delayed recall (β = 0.58, p = .037). White matter analyses revealed trends suggesting pregnancy-related reductions in fiber density and cross-section across multiple tracts, with 3-4 term pregnancies showing most consistent patterns. Hysterectomy showed trends toward higher fiber density in several tracts. Mediation analyses indicated white matter integrity did not account for reproductive-cognitive associations.

CONCLUSIONS: Reproductive history, particularly pregnancy number, is associated with cognitive performance and white matter microstructure in post-menopausal Latina women. These findings underscore the importance of considering reproductive factors in AD risk assessment and highlight the need for longitudinal studies to clarify mechanisms driving these associations.},
}

@article {pmid41310327,
year = {2025},
author = {Subramaniam, P and Singh, DKA and Al-Shahrani, HF and Hammad, MA and Lim, EV and Hoh, XJ and Tay, KW and Alavi, K},
title = {Effects of combined group reminiscence and exercise therapy on psychological wellbeing and functional fitness among older adults with dementia.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {42449},
pmid = {41310327},
issn = {2045-2322},
support = {2013-027//Pusat Transformasi Komuniti Universiti , Universiti Putra Malaysia/ ; PNURSP2025R707//Deanship of Scientific Research, Princess Nourah Bint Abdulrahman University/ ; },
mesh = {Humans ; Female ; Male ; Aged ; *Dementia/therapy/psychology ; *Exercise Therapy/methods ; Quality of Life ; Aged, 80 and over ; *Psychotherapy, Group/methods ; Treatment Outcome ; },
abstract = {Reminiscence therapy and exercise therapy have both proven beneficial for individuals with dementia. However, there is limited information on the effects of combining these two approaches in older adults with dementia. Our study aimed to investigate the impact of combined group reminiscence therapy (GRT) and group exercise therapy (GET) on psychological well-being and functional fitness in this population. A total of 32 older adults with mild to moderate dementia living in care homes were randomly assigned into either intervention or usual care groups. The study was conducted from January to June 2021. Intervention: Participants in intervention group received weekly an hour session of GRT and biweekly 1.25-hour session of GET. Reminiscence therapy was based on Remembering Yesterday and Caring Today module, adapted and modified according to participants' cultural background. GET consisted of stretching, strengthening, aerobic and multicomponent exercises. Outcome measures include the Quality of Life - Alzheimer's Disease (QOL-AD), Addenbrooke's Cognitive Examination-III (ACE-III), Beck Anxiety Inventory (BAI), Satisfaction with Life Scale (SWLS), Geriatric Depression Scale (GDS), and Functional Fitness MOT (FFMOT). Independent sample t-test and Mann-Whitney U test show that the participants from the GRT + GET group reported statistically significant higher quality of life and satisfaction with life, with a medium to large effect size. There are no other statistically significant results found for other psychosocial measures. FFMOT was found to deteriorate in both groups with a lesser amount in the intervention group. This study suggests that combined GRT and GET may induce some psychosocial benefits, in particular quality of life and some positive trend in deceleration of functional fitness deterioration among older adults with mild to moderate dementia. Preserving psychological and physical wellbeing is essential for older adults with dementia to maintain their functional independence for as long as possible.},
}

Humans
Female
Male
Aged
*Dementia/therapy/psychology
*Exercise Therapy/methods
Quality of Life
Aged, 80 and over
*Psychotherapy, Group/methods
Treatment Outcome

@article {pmid41310263,
year = {2025},
author = {Wu, Z and Mielke, MM and Murray, AM and Webb, K and Woods, RL and Owen, A and Orchard, SG and Chong, TT and Sheets, KM and Ryan, J},
title = {Plasma biomarkers of alzheimer's disease and related dementias are associated with cognitive change in community-dwelling older individuals in Australia and the US.},
journal = {GeroScience},
volume = {},
number = {},
pages = {},
pmid = {41310263},
issn = {2509-2723},
support = {U01AG029824/NR/NINR NIH HHS/United States ; U19AG062682/NR/NINR NIH HHS/United States ; 334047//National Health and Medical Research Council/ ; 1127060//National Health and Medical Research Council/ ; 1135727//National Health and Medical Research Council/ ; 1RF1AG079397/AG/NIA NIH HHS/United States ; },
abstract = {Plasma biomarkers of Alzheimer's disease and related dementias (ADRD) are associated with the risk of dementia. However, the extent to which they could reflect cognitive ageing, and whether this is consistent across factors known to influence biomarkers (e.g. sex and chronic kidney disease) and in different populations, is unknown. Data were from a diverse community-dwelling cohort of older individuals without dementia in Australia (n = 11,930) and the US (n = 1,181). Global cognition, verbal fluency, episodic memory and psychomotor speed were assessed repeatedly over more than a decade. Plasma phosphorylated tau181 (p-tau181), glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL) and amyloid beta (Aβ) 42 and 40 were measured using Simoa technology. Higher levels of p-tau181 (β: -0.001 to -0.212), GFAP (β: -0.022 to -0.300) and NfL (β: -0.022 to -0.219), and lower levels of Aβ42/40 ratio (β: 0.015 to 0.126) were associated with greater cognitive decline over time. Associations were strongest for global cognition, episodic memory, and psychomotor speed, and weaker/non-significant for verbal fluency. All associations were consistent across countries. Furthermore, in stratified analyses, the results did not differ by sex or depending on the presence of chronic kidney disease. We found robust associations between plasma ADRD biomarkers and cognitive change in initially healthy older individuals in both Australia and the US, and across both sexes. Despite chronic kidney disease influencing biomarker levels, associations were consistent among individuals with and without chronic kidney disease. This indicates the potential broad utility of these biomarkers.},
}

@article {pmid41310259,
year = {2025},
author = {Yokomizo, S and Maci, M and Stafford, AM and Miller, MR and Perle, SJ and Inagaki, S and Takahashi, S and Brown-Harding, H and Liang, L and Lovely, A and Algamal, M and Gillani, RL and Zwang, TJ and Richardson, D and Naegele, JR and Vogt, D and Kastanenka, KV},
title = {Transplantation of GABAergic Interneuron Progenitors Restores Cortical Circuit Function in an Alzheimer's Disease Mouse Model.},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
volume = {},
number = {},
pages = {e11472},
doi = {10.1002/advs.202511472},
pmid = {41310259},
issn = {2198-3844},
support = {R01AG066171/NH/NIH HHS/United States ; R21AG075807/NH/NIH HHS/United States ; //Japan Agency for Medical Research and Development/ ; 202360054//Japan Society for the Promotion of Science/ ; },
abstract = {In addition to dementia, Alzheimer's patients suffer from sleep impairments and aberrations in sleep-dependent brain rhythms. Deficits in inhibitory GABAergic interneuron function disrupt one of those rhythms, slow oscillation in particular, and actively contribute to Alzheimer's progression. The degree to which transplantation of healthy donor interneuron progenitors restores slow oscillation rhythm in young APP/PS1 mice is tested. Medial ganglionic eminence (MGE) progenitors are harvested from mouse embryos and transplanted them into host APP/PS1 mutant cortices. 3D light-sheet and structured illumination microscopy revealed that transplanted MGE progenitors survived and matured into healthy interneurons. In vivo multiphoton calcium imaging and voltage-sensitive dye imaging showed functional integration and slow oscillation rescue in the absence or presence of optogenetic stimulation. The work provides proof-of-concept evidence that stem cell therapy may serve as a viable strategy to rescue functional impairments in cortical circuits of APP/PS1 mice and potentially those of Alzheimer's patients.},
}

@article {pmid41310166,
year = {2025},
author = {Tran, T and Fu, M and Fung, J and Sankararaman, S and Elashoff, DA and Vossel, K and Chang, TS},
title = {Fair positive unlabeled learning for predicting undiagnosed Alzheimer's disease in diverse electronic health records.},
journal = {NPJ digital medicine},
volume = {8},
number = {1},
pages = {730},
pmid = {41310166},
issn = {2398-6352},
support = {R01AG085518-01A1//National Institute of Aging/ ; R01AG085518-01A1//National Institute of Aging/ ; R01AG085518-01A1//National Institute of Aging/ ; R01AG085518-01A1//National Institute of Aging/ ; R01AG085518-01A1//National Institute of Aging/ ; R01AG085518-01A1//National Institute of Aging/ ; CAREER-1943497//National Science Foundation/ ; R35GM153406/NH/NIH HHS/United States ; R01AG081768A/NH/NIH HHS/United States ; Contract #22-10079//California Department of Public Health, Chronic Disease Control Branch, Alzheimer's Disease Program/ ; Contract #22-10079//California Department of Public Health, Chronic Disease Control Branch, Alzheimer's Disease Program/ ; Contract #22-10079//California Department of Public Health, Chronic Disease Control Branch, Alzheimer's Disease Program/ ; U54NS123746/NS/NINDS NIH HHS/United States ; },
abstract = {Alzheimer's Disease (AD), the most common neurodegenerative disease, is underdiagnosed and more prominent in underrepresented groups. We performed semi-supervised positive unlabeled learning (SSPUL) coupled with racial bias mitigation for equitable prediction of undiagnosed AD from diverse populations at UCLA Health using electronic health records. SSPUL achieved superior sensitivity (0.77-0.81) and area under the precision recall curve (AUCPR) (0.81-0.87) across non-Hispanic white, non-Hispanic African American, Hispanic Latino, and East Asian groups compared to supervised baseline models (sensitivity: 0.39-0.53; AUCPR: 0.3-0.7). SSPUL also exhibited superior fairness as evidenced by the lowest cumulative parity loss. We identified top shared and distinct features among labeled and unlabeled AD patients, including those that are neurological (e.g., memory loss) and non-neurological (e.g., decubitus ulcer). We validated our results using polygenic risk scores, which were higher in labeled and predicted positives than in predicted negatives among non-Hispanic white, Hispanic Latino, and East Asian groups (p < 0.001).},
}

@article {pmid41309536,
year = {2025},
author = {Lei, MH and Cao, LJ and Liu, R and Zhang, YE and Zhang, SR and Zhuang, LY and Mo, YJ and Cheng, L and Lai, QL and Qiao, S},
title = {The evolving etiologies of rapidly progressive dementia: a systematic review.},
journal = {Translational psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41398-025-03777-7},
pmid = {41309536},
issn = {2158-3188},
support = {LQ23H090004//Natural Science Foundation of Zhejiang Province (Zhejiang Provincial Natural Science Foundation)/ ; },
abstract = {BACKGROUND AND PURPOSE: Rapidly progressive dementia (RPD) represents a heterogeneous group of clinical dementia syndromes characterized by a precipitous decline in cognitive function, typically occurring over weeks to months, with diverse underlying etiologies. To elucidate the evolving etiological spectrum of RPD and investigate temporal trends, we conducted a comprehensive systematic review incorporating temporal subgroup analyses.

METHOD: English-language studies published prior to December 31, 2024 were searched in the Medline (PubMed), ISI Web of Science and the Cochrane Library databases. Study design, study period, patient characteristics, etiologies of RPD in each study were retrieved.

RESULT: We encompassed 13 studies in our final systematic review, involving a total of 1,701 patients with RPD. Our findings revealed that neurodegenerative diseases (459 cases, 27.0%), neuroimmune diseases (327 cases, 19.2%), and central nervous system infections (295 cases, 17.3%) represented the most prevalent etiological categories associated with RPD. Among distinct disease entities, autoimmune encephalitis (AE, 266 cases, 15.6%), Alzheimer's disease (214 cases, 12.6%), and Creutzfeldt-Jakob disease (214 cases, 12.6%) were identified as the three most frequently observed etiologies of RPD. Temporally, neuroimmune diseases, particularly AE, exhibited a significant upward trend in prevalence over the study period.

CONCLUSION: These findings highlight the evolving etiological spectrum of RPD and emphasize the need for ongoing research and targeted diagnostic strategies to address the rising incidence of neuroimmune-related RPD.},
}

@article {pmid41309440,
year = {2025},
author = {Yadav, A and Dhawan, U},
title = {SpecQuality: A Tool for Reliable Spectral Quality Assessment in Proteomics and Proteogenomics.},
journal = {Journal of the American Society for Mass Spectrometry},
volume = {},
number = {},
pages = {},
doi = {10.1021/jasms.5c00168},
pmid = {41309440},
issn = {1879-1123},
abstract = {Proteogenomics integrates genomics and mass spectrometry (MS) data to understand complex biological systems, disease mechanisms, and potential biomarkers. However, the high volume and noise in MS data present computational and interpretational challenges in proteogenomic studies where, despite best efforts, many spectra are often left unassigned. We developed SpecQuality, an easy-to-use tool for MS/MS quality assessment. We evaluated ten spectral features and, using the top features, developed a machine learning-based model to predict the quality of MS/MS spectra through a spectral quality score (SQS). SpecQuality can be used prior to database search or for postsearch validation of peptide spectrum matches (PSMs). This enables rapid prioritization of high-quality PSMs from proteomics and proteogenomics searches, thereby reducing false-positive identifications. We demonstrated its utility in proteogenomics applications by evaluating its performance on two data sets with ∼2.7 million spectra from Alzheimer's disease, where it successfully highlighted high quality spectra. The spectra that matched novel, variant, and modified peptides in the proteogenomics search were observed to be of high spectral quality. Additionally, a direct comparison with manually curated variant identifications demonstrated its capacity to mitigate false positives and enhance reliability. SpecQuality is an open-source, freely available, easy-to-use, simple, and versatile tool developed in both Python and Perl that can be leveraged in many proteomics pipelines. It can be easily used as a standalone tool or integrated as a part of a bioinformatics data analysis pipeline. SpecQuality provides a scalable and accessible approach to spectral prioritization, advancing data integrity in proteomics and proteogenomics. SpecQuality is available at https://github.com/alkayadav10/SpecQuality.},
}

@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 {pmid41309397,
year = {2025},
author = {Garcia Condado, J and Verdugo Recuero, I and Elorriaga, IT and Birkenbihl, C and Carrigan, M and Diez, I and Buckley, RF and Erramuzpe, A and Cortes, JM and , },
title = {Corrigendum to "Aging as an active player in Alzheimer's disease classification: Insights from feature selection in BrainAge models" [NeuroImage (2025): 121548].},
journal = {NeuroImage},
volume = {},
number = {},
pages = {121604},
doi = {10.1016/j.neuroimage.2025.121604},
pmid = {41309397},
issn = {1095-9572},
}

@article {pmid41309383,
year = {2025},
author = {Anagnostakis, F and Kokkorakis, M and Nagarajan, S and Anastasiou, G and Mantzoros, CS},
title = {Comparative effectiveness of SGLT2 sodium-glucose cotransporter-2 inhibitors and GLP-1 glucagon-like peptide-1 receptor agonists for incident dementia: A retrospective multicohort study.},
journal = {Diabetes, obesity & metabolism},
volume = {},
number = {},
pages = {},
doi = {10.1111/dom.70336},
pmid = {41309383},
issn = {1463-1326},
abstract = {OBJECTIVE: This study provides real-world evidence on the comparative effectiveness of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT2i) regarding the risk of incident dementia in adults with type 2 diabetes mellitus (T2DM).

RESEARCH DESIGN AND METHODS: This cohort study utilised electronic health records from TriNetX (1 April 2013 to 31 December 2019). Adults with T2DM on metformin who initiated GLP-1 RAs or SGLT2i were analysed using Cox proportional hazards models in 1:1 propensity score-matched cohorts. The primary outcome was all-cause dementia; secondary outcomes included vascular and Alzheimer's dementia. Confounding variables were adjusted.

RESULTS: Among 16 271 participants using GLP-1 RAs and 16 271 using SGLT2i over a median 6.3-year follow-up, 581 GLP-1 RA users and 572 SGLT2i users developed dementia. No significant differences were observed in all-cause dementia (hazard ratio: 1.01, 95% confidence interval: 0.90-1.13), vascular, or Alzheimer's dementia. Subgroup analyses confirmed these findings.

CONCLUSIONS: SGLT2i use was not associated with increased risk of dementia compared with GLP-1RAs in patients with T2DM. Further research is warranted to explore the effects of (newer) incretin-based (co-)agonists on cognitive outcomes.},
}

@article {pmid41309199,
year = {2025},
author = {Chinnathambi, S and Dubey, T and Rangappa, N},
title = {The calpain-mediated proteolytic cleavage peptide P10 modulates Tau phosphorylation in Alzheimer's disease.},
journal = {Advances in protein chemistry and structural biology},
volume = {148},
number = {},
pages = {481-505},
doi = {10.1016/bs.apcsb.2025.08.009},
pmid = {41309199},
issn = {1876-1631},
mesh = {*Alzheimer Disease/metabolism/pathology/drug therapy ; Humans ; *tau Proteins/metabolism ; Phosphorylation/drug effects ; *Calpain/metabolism ; Proteolysis ; Cyclin-Dependent Kinase 5/metabolism/antagonists & inhibitors ; Animals ; },
abstract = {Alzheimer's disease is a prominent neurological disorder, which leads to progressive dementia. The microtubule-associated protein Tau is considered one of the major causes of Alzheimer's disease. Hyper-phosphorylation of Tau is considered to be closely associated with the generation of Tau pathology. CDK5 is one of the prominent neuronal kinases, under normal conditions, the activity of CDK5 is regulated by p35 protein. The stress conditions result in calpain-mediated proteolytic cleavage of p35 leading to the generation of p25 and p10. CDK5/p25 complex is reported to have a relatively more half-life which causes hyperphosphorylation of many proteins leading to neurotoxicity but the role of p10 is still needed to be explored. In the present review, we hypothesized the role of p10 as CDK5/p25 inhibitor. The current research has demonstrated that p10 provides survival signals to cells. In the current scenario, several CDK5 inhibitors commonly have a drawback of non-specificity. Here based on complied studies we hypothesize that the p10 could have the potency to inhibit the activity of CDK5, which ultimately downregulate the hyperphosphorylation of Tau. Thus reducing the levels of phospho-Tau p10 could emerge as a novel therapeutic peptide against Alzheimer's disease. The proposed hypothesis would open new gates for research in the field of Alzheimer's and further would bring a new ray of hope for the disease.},
}

*Alzheimer Disease/metabolism/pathology/drug therapy
Humans
*tau Proteins/metabolism
Phosphorylation/drug effects
*Calpain/metabolism
Proteolysis
Cyclin-Dependent Kinase 5/metabolism/antagonists & inhibitors
Animals

@article {pmid41309198,
year = {2025},
author = {Sood, A and Dey, M and Tyagi, A and Sharma, DK and Mehrotra, A},
title = {Chaperone machinery in neurodegeneration: A spotlight on protein misfolding diseases.},
journal = {Advances in protein chemistry and structural biology},
volume = {148},
number = {},
pages = {455-480},
doi = {10.1016/bs.apcsb.2025.08.007},
pmid = {41309198},
issn = {1876-1631},
mesh = {Humans ; *Proteostasis Deficiencies/metabolism/pathology ; *Neurodegenerative Diseases/metabolism/pathology ; *Molecular Chaperones/metabolism ; Protein Folding ; Animals ; },
abstract = {Proteins misfolding in neurodegenerative disorders pose a significant challenge to human health and this necessitates a deeper understanding of the fundamental molecular mechanisms. Molecular chaperones are a diverse group of specialized proteins, which are extensively involved in maintaining cellular protein homeostasis and thus preventing aggregation of misfolded proteins. Pathological advancement in several neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease (PD) and Huntington's disease (HD) is characterized by the rampant accretion of misfolded proteins due to chaperonic failure, leading to progressive neuronal dysfunctioning and eventually cell death. Such as in AD, Hsp70 and Hsp90 chaperones are known to interact with β-amyloid and tau proteins, thus preventing their subsequent aggregation with concomitant refolding into native conformations. In PD, chaperones are involved in assisting mitigation of α-Syn misfolding and aggregation, thereby maintaining the normal neuronal functions and their viability. Similarly in HD, chaperones modulate aberrant misfolding of huntingtin protein and its aggregation, thus highlighting prospective therapeutic targets for disease intervention. Nevertheless, further investigating and understanding the explicit roles of chaperones in modulating several protein misfolding diseases holds potential for the development of novel therapeutic approaches. Moreover, targeting such specialized chaperone machinery in restoring protein homeostasis and alleviating subsequent protein aggregation could be considered as a promising approach in managing neurodegenerative disorders.},
}

Humans
*Proteostasis Deficiencies/metabolism/pathology
*Neurodegenerative Diseases/metabolism/pathology
*Molecular Chaperones/metabolism
Protein Folding
Animals

@article {pmid41309196,
year = {2025},
author = {Jamwal, RS and Sharma, B and Minerva, and Gupta, A and Misri, S and Shankaryan, R and Shah, R and Kumar, R},
title = {Protein misfolding and its dual role in neurodegeneration and cancer progression.},
journal = {Advances in protein chemistry and structural biology},
volume = {148},
number = {},
pages = {355-377},
doi = {10.1016/bs.apcsb.2025.10.001},
pmid = {41309196},
issn = {1876-1631},
mesh = {Humans ; *Neoplasms/metabolism/pathology ; *Protein Folding ; *Neurodegenerative Diseases/metabolism/pathology ; Animals ; Disease Progression ; Unfolded Protein Response ; },
abstract = {Protein misfolding is a fundamental biological process with profound implications for human health and disease. Typically, proteins assume precise three-dimensional structures to perform their functions, a process safeguarded by the proteostasis network, which comprises molecular chaperones, the ubiquitin-proteasome system (UPS), and autophagy. However, genetic mutations, oxidative stress, and environmental insults can disrupt folding, leading to the accumulation of non-functional or toxic conformations. In neurodegenerative diseases such as Huntington's disease (HD), Parkinson's disease (PD), Alzheimer's disease (AD), Amyotrophic lateral Sclerosis (ALS), chronic misfolding results in toxic protein aggregates like amyloid-β, tau, and α-synuclein. These disrupt synaptic function, induce oxidative and nitrosative stress, and trigger apoptosis, ultimately leading to progressive neuronal loss. Dysregulation of the unfolded protein response (UPR) and weakened proteostasis with aging exacerbate disease pathology. In contrast, cancer cells utilize protein misfolding to enhance their survival and progression. Misfolded oncoproteins, such as mutant p53, not only evade degradation but also acquire oncogenic properties. Tumor cells hijack the UPR and chaperone networks, upregulate heat shock proteins, and manipulate oxidative stress responses to withstand hypoxia, nutrient deprivation, and rapid proliferation. Cancer stem cells (CSCs) further adapt to proteotoxic stress, contributing to tumor heterogeneity, therapy resistance, and immune evasion. The dual role of protein misfolding, driving degeneration in neurons while supporting proliferation in tumors, underscores its centrality in disease biology. Future research should focus on identifying early biomarkers of proteostasis imbalance and exploiting shared molecular pathways for the development of novel therapeutic interventions.},
}

Humans
*Neoplasms/metabolism/pathology
*Protein Folding
*Neurodegenerative Diseases/metabolism/pathology
Animals
Disease Progression
Unfolded Protein Response

@article {pmid41309195,
year = {2025},
author = {Nair, T and Sarkar, D and Murmu, S and Singh Rawat, R and Singha, B},
title = {Proteostasis and pathogenesis: Unraveling the complexity of protein misfolding disorders.},
journal = {Advances in protein chemistry and structural biology},
volume = {148},
number = {},
pages = {299-353},
doi = {10.1016/bs.apcsb.2025.08.013},
pmid = {41309195},
issn = {1876-1631},
mesh = {Humans ; *Proteostasis Deficiencies/metabolism/pathology ; *Proteostasis ; Protein Folding ; Animals ; Protein Processing, Post-Translational ; Molecular Chaperones/metabolism ; *Neurodegenerative Diseases/metabolism/pathology ; },
abstract = {Within the cellular milieu, protein molecules must fold into precise three-dimensional structures to attain functionality. Protein chains can assume many misfolded states during this critical process. Such errant configurations are unstable and can aggregate into toxic misfolded conformations. In protein misfolding disorders, polypeptides are folded in an aberrant manner, resulting in non-functional and often pathogenic states. Protein folding is fundamental to biological function, and disruption of the process can result in toxic aggregates, such as oligomers and amyloid fibrils, which are implicated in a variety of diseases, particularly neurodegenerative diseases such as Alzheimer's and Parkinson's. Here, we examine the delicate interplay of forces that determine the native conformation of proteins and how perturbations in this balance lead to disease. A critical aspect of our discussion is the cell's proteostasis network, a complex network of molecular chaperones and regulators responsible for regulating protein folding and maintaining the health of the cell. In this chapter, we discuss how intrinsic protein properties, post-translational modifications, and extrinsic environmental factors can destabilize proteins, thereby resulting in their misfolding. Several pathogenic mechanisms will be elucidated, including the progression from a misfolded protein to the development of disease phenotypes. Next, the chapter will present an overview of the current therapeutic approaches to mitigate the diseases caused by protein misfolding. Using the latest findings in clinical and experimental research, we will evaluate the therapeutic landscape, ranging from small-molecule inhibitors to chaperone-based therapies.},
}

Humans
*Proteostasis Deficiencies/metabolism/pathology
*Proteostasis
Protein Folding
Animals
Protein Processing, Post-Translational
Molecular Chaperones/metabolism
*Neurodegenerative Diseases/metabolism/pathology

@article {pmid41309194,
year = {2025},
author = {Montaño, S and Luna-Viramontes, NI and Cuevas, E and Martínez-Cuevas, PP and Pacheco-Herrero, M and León-López, L and Armenta, AD and Luna-Muñoz, J},
title = {Unraveling tau's fold: Structural dynamics in Alzheimer's pathogenesis.},
journal = {Advances in protein chemistry and structural biology},
volume = {148},
number = {},
pages = {29-56},
doi = {10.1016/bs.apcsb.2025.08.005},
pmid = {41309194},
issn = {1876-1631},
mesh = {*tau Proteins/metabolism/chemistry ; Humans ; *Alzheimer Disease/metabolism/pathology ; Neurofibrillary Tangles/metabolism/pathology ; Phosphorylation ; Protein Processing, Post-Translational ; },
abstract = {Alzheimer's disease (AD), among the diseases associated with dementia, is the most prevalent. It has been estimated that over 55 million people older than 65 years-old are living with dementia worldwide. Two-thirds of the AD population are women. It is estimated that by 2050 there will be 139 million people with dementia. AD is a neurodegenerative, progressive and irreversible process, affecting the patient's daily life activities. The pathological neurodegenerative process of AD begins 15-20 years before the appearance of the first clinical symptoms. The histopathological analysis reveals the presence of neurofibrillary tangles (NFTs) and neuritic plaques [1] the main hallmarks of AD. In this work, we are describing the NFTs that are made up of paired helical filaments of tau protein, which undergo post-translational modifications such as hyperphosphorylation and truncation, favoring conformational changes of the molecule. The most relevant information about the pathological processing of the tau protein is presented, focusing on the truncation at Glu391 (minimal filament nucleus, PHF-core) as a pathological inducing event of the tau protein and as an early biomarker of AD. Based on reports and our evidence, we suggest that the hyperphosphorylated tau protein participates as the neuroprotective event against this highly toxic PHF-core.},
}

*tau Proteins/metabolism/chemistry
Humans
*Alzheimer Disease/metabolism/pathology
Neurofibrillary Tangles/metabolism/pathology
Phosphorylation
Protein Processing, Post-Translational

@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 {pmid41308985,
year = {2025},
author = {Yokoo, T and Nakakido, M and Matsuda, K and Caaveiro, JMM and Fernandez-Perez, J and Yuzaki, M and Tsumoto, K},
title = {Development of a VHH that inhibits the binding of neuronal pentraxin 2 to a post-synaptic glutamate receptor, AMPAR.},
journal = {The Journal of biological chemistry},
volume = {},
number = {},
pages = {110975},
doi = {10.1016/j.jbc.2025.110975},
pmid = {41308985},
issn = {1083-351X},
abstract = {Neurons connect to each other via synapses to form neural circuits. Recent research has shown that neuropsychiatric disorders and neurological disorders such as autism spectrum disorders and Alzheimer's disease (AD) are synaptic diseases caused by abnormality of synapses. Synaptic organizers are molecules responsible for synapse formation. Neuronal pentraxin 2 (NP2) is synaptic organizer and a secreted protein that is expressed mainly in the hippocampus and cerebellum, and it contributes to synaptic plasticity. NP2 forms clusters with its family proteins NP1 and NPR and binds to postsynaptic amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-type receptors (AMPARs). In recent years, research has revealed the disease relevance of NP2. For example, it can be a biomarker of AD, and its overexpression in the peripheral nervous system has been reported to cause chronic itch. However, the mechanism of NP2 function has not been well described at the molecular level. In this study, we developed a variable domain of heavy chain of heavy chain antibody (VHH) against NP2 to elucidate its molecular mechanism of action and to regulate its function of NP2. The obtained VHH N1 showed high specificity and affinity to NP2, and its binding mechanism was elucidated by X-ray crystallography. Furthermore, VHH N1 inhibited the binding of NP2 to AMPARs, and this inhibitory activity was confirmed in cells. These results provide useful insights into the molecular mechanism of NP2 function and highlight the potential application of VHH N1 as a detection agent for NP2 or as a therapeutic agent for chronic itch.},
}

@article {pmid41308879,
year = {2025},
author = {Jia, X and Li, M and Wang, Y and Li, H and Zhang, X and Chen, H and Tian, J and Zhang, G and Wang, T},
title = {Neural stem cells improve the function of learning and memory in the ibotenic acid-induced Alzheimer's disease mice.},
journal = {Behavioural brain research},
volume = {},
number = {},
pages = {115965},
doi = {10.1016/j.bbr.2025.115965},
pmid = {41308879},
issn = {1872-7549},
abstract = {Neural stem cells (NSCs) showed a promising approach to treat Alzheimer's disease (AD). This study aims to investigate whether mouse NSCs transplantation can improve the function of learning and memory of AD mouse model and the underlying mechanism. NSCs was stereotaxically injected into the hippocampi of ibotenic acid (IBO)-induced AD mice. Behavioral tests were conducted to evaluate neurological function. Golgi and immunofluorescence staining were used to assess the injury of the nerves. Additionally, enhanced green fluorescent protein (EGFP) labeling was employed to evaluate the differentiation of NSCs. Compared with model group, NSCs transplantation shortened the escape latency and increased the crossing platform quadrant time, number of crossing the platform (p < 0.01). The preference index and active avoidance rate was increased after NSCs transplantation when compared with the model group (p < 0.05 or p < 0.01). NSCs augmented not only the number of neurons in the hippocampal CA1 region, but also the dendritic spine density, dendritic complexity and ACh content in the hippocampus (p < 0.05 or p < 0.01). Furthermore, NSCs also elevated the levels of BDNF in the hippocampus of AD mice (p < 0.01). It also showed that a portion of transplanted NSCs differentiated into neurons at four weeks post-transplantation. These results demonstrated that NSCs improved learning and memory function in the AD model by ameliorating neuron injury and differentiating into neurons.},
}

@article {pmid41308841,
year = {2025},
author = {Wagaskar, P and Suryawanshi, M and Patil, A and Pardeshi, V},
title = {Therapeutic Potential of Third Molar-Derived Dental Pulp Stem Cells in Alzheimer's disease: Current Evidence and Future Directions.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {102949},
doi = {10.1016/j.arr.2025.102949},
pmid = {41308841},
issn = {1872-9649},
abstract = {Alzheimer's disease (AD), the most common cause of dementia, is characterized by amyloid-β deposition, tau hyperphosphorylation, neuroinflammation, and progressive neuronal loss, with no curative therapy currently available. Dental pulp stem cells (DPSCs) derived from third molars represent an ethically accessible, minimally invasive, neural crest-derived mesenchymal stem cell source with self-renewal and multi-lineage differentiation potential. Preclinical evidence suggests that DPSCs exert neuroprotective effects by reducing oxidative stress and apoptosis, enhancing neurogenesis through synaptic repair and neuronal differentiation, and modulating neuroinflammation via microglial regulation. Their secretion of neurotrophic factors, including BDNF, GDNF, NGF, NT-3, CNTF, and HGF, further supports neuronal survival and functional recovery in Alzheimer's disease models. Advances in 3D neurosphere and brain organoid models demonstrate the integration of DPSCs into neural circuitry, highlighting their translational potential. Nevertheless, challenges such as cell survival, migration, and functional integration within the diseased brain remain. Importantly, the use of extracted third molars avoids major ethical concerns associated with embryonic stem cells, making DPSCs a clinically relevant candidate for regenerative approaches. Future directions emphasize the development of exosome-based therapies, bioengineered scaffolds, gene-modified DPSC strategies, and personalized autologous interventions. Collectively, current evidence positions third molar-derived DPSCs as a promising avenue for disease-modifying and regenerative therapies in Alzheimer's disease.},
}

@article {pmid41308838,
year = {2025},
author = {Sultana, OF and Bandaru, M and Bushra, MA and Reddy, PH and Reddy, AP},
title = {Serotonin-mediated regulation of mitophagy in Alzheimer's disease: mechanistic insights and therapeutic potential.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {102957},
doi = {10.1016/j.arr.2025.102957},
pmid = {41308838},
issn = {1872-9649},
abstract = {This review delves into the intricate relationship between serotonin signaling, mitophagy and mitochondrial dysfunction in Alzheimer's disease (AD), with a focus on the mechanistic pathways that link these processes and their potential therapeutic implications. A neurodegenerative condition called Alzheimer's disease is marked by cognitive deterioration. It is increasingly recognized as being influenced by impaired mitochondrial function and mitophagy, the selective degradation of damaged mitochondria. Serotonin, a neurotransmitter traditionally known for its role in mood regulation, has emerged as a critical modulator of mitochondrial dynamics and quality control through its interaction with key pathways such as the PINK1-Parkin and cAMP/PKA signaling pathways. In AD, alterations in serotonin levels and receptor function are associated with disruptions in mitophagy, leading to the accumulation of dysfunctional mitochondria, increased oxidative stress, and subsequent neuronal damage. This review synthesizes current evidence that links serotonin dysregulation to mitochondrial pathology in AD, exploring how impaired serotonin signaling exacerbates mitochondrial dysfunction and contributes to amyloid-beta (Aβ), phosphorylation of Tau (p-Tau) accumulations, and increased neuroinflammation. Additionally, we assessed the therapeutic potential of serotonin-targeting agents, particularly selective serotonin reuptake inhibitors (SSRIs), in restoring mitophagy, enhancing mitochondrial integrity, and attenuating neurodegeneration. By highlighting existing knowledge gaps and key controversies, this review underscores the promise of serotonin-mitochondria pathways as novel therapeutic targets and advocates for focused investigation into receptor-specific, mitophagy-centered interventions for AD.},
}

@article {pmid41308758,
year = {2025},
author = {Zhong, L and Zhao, L and Tang, Q and Zhang, X and Zhou, M and Luo, J and Wang, Y},
title = {Multifunctionality of tissue inhibitor of metalloproteinase-1 in central nervous system diseases.},
journal = {Brain research bulletin},
volume = {},
number = {},
pages = {111647},
doi = {10.1016/j.brainresbull.2025.111647},
pmid = {41308758},
issn = {1873-2747},
abstract = {Central nervous system (CNS) diseases are characterized by high morbidity, long disease courses, and irreversible neurological impairment, often resulting from damage to the neurovascular unit (NVU). Tissue inhibitor of metalloproteinase-1 (TIMP-1), the endogenous inhibitor of matrix metalloproteinase-9 (MMP-9), plays a pivotal role in maintaining extracellular matrix (ECM) homeostasis and regulating NVU integrity. Beyond its canonical MMP-inhibitory function, TIMP-1 exerts a wide spectrum of MMP-independent effects as a multifunctional cytokine that interacts with cell surface receptors such as CD63/β1-integrin and low-density lipoprotein receptor-related protein-1 (LRP-1). Through activation of FAK/PI3K-Akt and MAPK signaling pathways, TIMP-1 modulates astrocyte proliferation, neural stem cell adhesion and migration, endothelial barrier stability, and myelin regeneration. Altered TIMP-1 expression is closely associated with the onset, progression, and prognosis of major CNS disorders, including ischemic stroke, epilepsy, multiple sclerosis, and neurodegenerative diseases such as Alzheimer's and Parkinson's disease. Accumulating evidence highlights its dual, context-dependent roles-protective in acute neuroinflammatory and ischemic injury, yet potentially profibrotic or maladaptive under chronic pathological conditions. This review comprehensively summarizes recent advances in understanding the molecular mechanisms and biological functions of TIMP-1 in CNS diseases, emphasizing its regulatory networks in neuroinflammation, neuroprotection, and neuroregeneration. A deeper understanding of TIMP-1 signaling dynamics will accelerate its translational application as a diagnostic biomarker and therapeutic target for restoring neurovascular unit function in CNS disorders.},
}

@article {pmid41308741,
year = {2025},
author = {Yang, Y and Yu, Z and Gao, R and Zhang, Y and Zhang, Z and Zhong, X and Jiao, L and Du, K and Wu, Y and Wei, M and Liu, M},
title = {Novel protein acylations in Alzheimer's disease: molecular, mechanisms, biological significance, and diagnostic and therapeutic potentials.},
journal = {Journal of advanced research},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jare.2025.11.050},
pmid = {41308741},
issn = {2090-1224},
abstract = {BACKGROUND: Alzheimer's disease (AD) is a prevalent neurodegenerative disorder characterized by complex pathogenesis including amyloid-β (Aβ), hyperphosphorylated tau mediated neurofibrillary tangles (NFTs), energy metabolism disorders, and neuroinflammation, imposing significant burdens on patients' families and society. Increasing evidence implicates epigenetic modifications, particularly novel protein acylations, encompassing endogenous energy metabolites- mediated lysine succinylation (Ksucc), propionylation (Kpr), malonylation (Kmal), crotonylation (Kcr), butyrylation (Kbu), 2-hydroxyisobutyrylation (Khib), β-hydroxybutyrylation (Kbhb), and glutarylation (Kglu), lactylation (Kla), alongside benzoylation (Kbz) mediated by sodium benzoate metabolites and isonicotinylation (Kinic) induced by isoniazid, playing a pivotal role in AD pathogenesis.

AIM OF REVIEW: To enhance the mechanistic understanding of novel acylations, this review systematically summarizes the molecular biological significance of novel protein acylations and their involvement in AD pathogenesis and improvement.

Novel acylations exert profound effects on chromatin architecture, DNA accessibility, and transcriptional regulation. Moreover, they critically coordinate protein properties and functions including modulating protein degradation, protein stability, enzyme activity, protein-protein interaction, and subcellular localization. Dysregulation of specific novel acylations orchestrates key cellular processes such as neuroinflammation, metabolic dysfunction, and programmed cell death, thereby contributing to AD progression. This review systematically delineates the mechanistic foundations of novel acylation modifications and underscores their molecular significance. Furthermore, we comprehensively synthesize current knowledge on the involvement of these acylations in AD, offering novel perspectives for developing targeted preventive and therapeutic strategies.},
}

@article {pmid41308510,
year = {2025},
author = {Braak, S and Oldehinkel, M and Mennes, M and Su, T and Pijnenburg, Y and Arango, C and Ayuso-Mateos, JL and van der Wee, N and Dawson, GR and Marston, HM and Beckmann, CF and Kas, MJH and Penninx, BWJH},
title = {Default mode network integrity across neuropsychiatric disorders and its relation to social dysfunction: A normative modelling approach.},
journal = {European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology},
volume = {102},
number = {},
pages = {28-38},
doi = {10.1016/j.euroneuro.2025.11.002},
pmid = {41308510},
issn = {1873-7862},
abstract = {Structural and functional default mode network (DMN) alterations are common in neuropsychiatric disorders and may contribute transdiagnostically to social dysfunction. Normative modelling enables assessment of DMN alterations at the individual level. This study investigates whether individual deviations in cortical thickness, surface area, and between-network functional connectivity of the DMN differ between schizophrenia (SZ), major depressive disorder (MDD), Alzheimer's disease (AD), and healthy controls (HC), and whether these deviations transdiagnostically relate to social dysfunction. Social dysfunction was assessed using a composite score from the Social Functioning Scale and De Jong-Gierveld Loneliness scale. Structural MRI data was collected for 329 participants (SZ=86, MDD=44, AD=82, HC=117) and resting-state fMRI data for 317 participants. Individual deviation scores of DMN integrity were computed by adapting existing normative models of cortical thickness (N = 58,836), surface area (N = 43,524), and between-network functional connectivity (N = 21,515). Extreme deviations were quantified using a z-threshold of ±1.96. DMN deviation scores were not transdiagnostically associated with social dysfunction across the sample (ps>0.05). AD patients had more extreme negative deviations in DMN cortical thickness than all other groups (ps<0.0001; z = -4.14 to -6.34) and fewer extreme positive deviations in DMN surface area relative to SZ and HC (ps<0.05; z = 2.10 to 2.71). For between-network functional connectivity of the DMN, AD and SZ patients had more extreme negative deviations than MDD and HC (ps<0.05; z = -2.09 to -3.54). To conclude, normative modelling reveals differences in individual deviations of DMN integrity between neuropsychiatric groups, but these deviations do not transdiagnostically relate to social dysfunction.},
}

@article {pmid41308405,
year = {2025},
author = {Lee, WM and Ryu, SI and Lim, MN and Han, JW and Bae, JB and Kim, TH and Kwak, KP and Kim, BJ and Kim, SG and Kim, JL and Moon, SW and Park, JH and Ryu, SH and Lee, DW and Lee, SB and Lee, JJ and Lee, DY and Kim, KW and Jhoo, JH},
title = {Association Between Omega-3 Supplement Use and Cognitive Function in Korean Older Adults: An 8-Year Longitudinal Cohort Study.},
journal = {The journal of nutrition, health & aging},
volume = {30},
number = {1},
pages = {100739},
doi = {10.1016/j.jnha.2025.100739},
pmid = {41308405},
issn = {1760-4788},
abstract = {OBJECTIVES: South Korea has a relatively high baseline omega-3 fatty acids (O3FA) status due to dietary patterns. However, evidence on additional benefits of O3FA supplementation remains limited. This study examined the 8-year longitudinal effects of O3FA supplement use on cognitive performance among community-dwelling older adults in South Korea.

DESIGN: Prospective longitudinal cohort study.

SETTING AND PARTICIPANTS: Data were from the Korean Longitudinal Study on Cognitive Aging and Dementia (KLOSCAD). A total of 4,949 adults aged ≥60 years (mean age = 69.55 ± 6.56; 44.2% men) were included, and 2,053 completed the 8-year follow-up (2010-2012 to 2018-2020).

MEASUREMENTS: O3FA supplement use was assessed through structured questionnaires on regular intake of omega-3 or fish oil supplements. Cognitive performance was assessed using the Korean version of Consortium to Establish a Registry for Alzheimer's Disease Assessment Packet Neuropsychological Assessment Battery (CERAD-K[N]), and total and memory domain scores were analyzed. Longitudinal changes were examined using repeated measures analysis of covariance and linear mixed-effects models (LMMs; unweighted and weighted), adjusting for potential covariates.

RESULTS: Over the 8 years, CERAD-K[N] (t = -2.686, p = .007) and memory domain (t = -4.026, p < .001) scores significantly improved among O3FA users. In the weighted LMM, significant time × supplement duration interactions were observed (CERAD-K[N]: β = 2.398, 95% CI 1.207-3.589, p < .001; memory: β = 1.050, 95% CI 0.643-1.456, p < .001), indicating greater improvement in long-term users.

CONCLUSION: O3FA supplement use was associated with better maintenance of cognitive function over eight years. These findings suggest a potential role of O3FA supplementation in supporting cognitive health during aging.},
}

@article {pmid41308018,
year = {2025},
author = {Zhou, W and Lin, H and Huang, X and Zhou, X},
title = {Identification and validation of PANoptosis-related genes in Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251396927},
doi = {10.1177/13872877251396927},
pmid = {41308018},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD) is the main cause of dementia in older adults. Recently, increasing evidence shows that PANoptosis plays an important role in AD.ObjectiveThis study investigated potential roles of PANoptosis by bioinformatics and machine learning in AD.MethodsAD-related microarray sets were downloaded from the GEO database and PANoptosis-related genes were extracted from the GeneCards database. By WGCNA and constructing machine learning models, hub genes were identified and verified. A ceRNA network was established using cytoscape. The ssGSEA was used to estimate immune cell infiltration and its correlation with hub genes. The R package was performed for consensus clustering (CC) analysis.Results240 differentially expressed genes in the training set were identified. By selecting optimal models, we finally identified five PANoptosis-related hub genes in AD: ADCYAP1, BCL6, CXCR4, SPP1, and PGF, which were verified in the validation set (excluding SPP1 unverified) and the Aβ25-35-induced AD cell model. Subsequently, a risk prediction model with good performance for AD and a ceRNA network was established. Then, it was found that 14 types of immune cells with increased expression and 5 types with decreased expression in AD, significantly related to hub genes. Finally, two AD subtypes were proposed based on CC analysis: high immune infiltrative (more immune cell expression associated with inflammation and programmed cell death pathways) and low immune infiltrative subtype.ConclusionsOur results suggest that five PANoptosis-related genes are significantly associated with the pathologic progression of AD; we proposed two AD immune infiltrative subtypes.},
}

@article {pmid41308015,
year = {2025},
author = {Usher, MR and Aybar-Torres, AA and Jin, L},
title = {Identification of common human TMEM173 genotypes associated with Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251396973},
doi = {10.1177/13872877251396973},
pmid = {41308015},
issn = {1875-8908},
abstract = {BackgroundRecent animal studies have revealed STING (Stimulator of interferon genes) as a potential key player in Alzheimer's disease (AD). The actual impact of human STING on AD, however, is unknown. Mouse STING studies were done in WT/WT. However, TMEM173, the human gene encodes STING, has 5 common, distinct, sometimes opposite functional alleles that result in 25 TMEM173 genotypes. Only ∼50% of whites, 36% of African Americans (AA), 22% of East Asians are WT/WT. Past STING cancer immunotherapy clinic trials, which did not consider human TMEM173 heterogeneity, all failed.Objective(1) Discover new protective and risk AD genetic factors across populations or AA-specific. (2) Establish the physiological significance of common human TMEM173 genotypes and human diseases.MethodsWe conduct a large-scale (∼15,000 individuals) case-control analysis between TMEM173 genotypes and AD using data from The National Institute on Aging Genetics of Alzheimer's Disease Data Storage Site. The data include late-onset AD (LOAD) non-Hispanic White (NHW), early-onset AD (EOAD) NHW, and AA.ResultsA common H232/HAQ TMEM173 genotype is associated with AD protection across the populations. An AA-specific TMEM173 genotype H232/Q293 increases the risk for AA males (OR = 17.7148), especially in the APOE ε3/ε3 population.ConclusionsThe findings discovered the first AA-specific high AD risk factor and established an association between human TMEM173 and AD, paving the way for STING-targeting effective AD healthcare.},
}

@article {pmid41308013,
year = {2025},
author = {Zhu, X and Zhang, L and Qin, C},
title = {Hub genes and diagnostic model associated with mitochondrial function in Alzheimer's disease.},
journal = {Animal models and experimental medicine},
volume = {},
number = {},
pages = {},
doi = {10.1002/ame2.70104},
pmid = {41308013},
issn = {2576-2095},
support = {2023-PT180-01//Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences/ ; 2023-PT330-01//Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences/ ; 2021-I2M-1-034//Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences/ ; 82161138027//National Natural Science Foundation of China/ ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) represents the most prevalent neurodegenerative disorder, with mitochondrial dysfunction being observed in both AD patients and mouse models. Nonetheless, further investigation is required to elucidate the pathogenic genes associated with AD and to develop early diagnostic methodologies centered on mitochondrial function.

METHODS: In this study, the dataset GSE132903 was retrieved from the GEO database, encompassing both non-demented (ND) control and AD samples. Through the combination of differential expression gene analysis, weighted gene co-expression network analysis, and intersection with mitochondrial database gene sets, four hub genes associated with AD were identified. These four hub genes were subsequently validated in APP/PS1 and 5xFAD mouse models using molecular biology techniques.

RESULTS: The hub genes identified through bioinformatics analysis include SYNJ2BP, VDAC1, NUBPL, and COX19. Within the GSE132903 dataset, the expression levels of SYNJ2BP, NUBPL, and COX19 were significantly elevated in the AD group compared to the non-demented (ND) group, whereas VDAC1 expression was reduced in the AD group relative to the ND group. Furthermore, in the hippocampus of APP/PS1 and 5xFAD mouse models, the expression patterns of SYNJ2BP and NUBPL were consistent with the bioinformatics analysis results.

CONCLUSION: Hub genes identified here through bioinformatics and molecular biology may help early diagnosis of AD patients and may also help build new AD models to explore its pathogenesis.},
}

@article {pmid41307999,
year = {2025},
author = {Tsai, AP and Henze, DE and Ramirez Lopez, E and Haberberger, J and Dong, C and Lu, N and Atkins, M and Costa, EK and Farinas, A and Oh, HS and Moran-Losada, P and Le Guen, Y and Isakova, A and Quake, SR and Wyss-Coray, T},
title = {Spatial and single-cell transcriptomics reveal the reorganization of cerebellar microglia with aging.},
journal = {Cell reports},
volume = {44},
number = {12},
pages = {116624},
doi = {10.1016/j.celrep.2025.116624},
pmid = {41307999},
issn = {2211-1247},
abstract = {The cerebellum, essential for motor coordination and increasingly recognized for its role in cognition, is typically considered more resilient to aging and largely spared from hallmark Alzheimer's disease (AD) pathology. However, transcriptomic analyses across fifteen mouse brain regions revealed that the cerebellum undergoes some of the earliest and most pronounced age-related changes. To investigate cerebellar aging, we applied single-nucleus RNA sequencing (RNA-seq), microglial bulk RNA-seq, and multiplexed error-robust fluorescence in situ hybridization (MERFISH)-based spatial transcriptomics. Microglia showed the most prominent changes, including elevated expression of a neuroprotective signature and reduced expression of a lipid-droplet-accumulating signature compared to hippocampal microglia. Spatial analyses further revealed that aged cerebellar microglia were positioned in close proximity to granule cells. Utilizing this relationship, we identified a proximity-dependent transcriptional state defined by the neuron-associated microglial signature. This signature reveals a region-specific microglial adaptation, highlighting cerebellar reorganization with age and potential resilience to AD.},
}

@article {pmid41307953,
year = {2025},
author = {Gong, Z and Laporte, JP and Guo, AY and Bilgel, M and Bae, J and Fox, NY and de Rouen, A and Zhang, N and Taranath, A and de Cabo, R and Egan, JM and Ferrucci, L and Bouhrara, M},
title = {Early axonal degeneration linked to clinical decline in Alzheimer's disease progression revealed with diffusion MRI.},
journal = {The Journal of clinical investigation},
volume = {},
number = {},
pages = {},
doi = {10.1172/JCI196638},
pmid = {41307953},
issn = {1558-8238},
abstract = {BACKGROUND: Axonal degeneration is believed to be an early hallmark of Alzheimer's disease (AD). This study investigated the temporal trajectory of axonal loss and its association with cognitive and functional decline using diffusion MRI-derived Axonal Density Index (dMRI-ADI).

METHODS: Longitudinal dMRI, CSF and PET data from the ADNI were analyzed, including 117 cognitively normal (CN) and 88 impaired (CI) subjects, consisting of 74 mild cognitive impairment (MCI) and 14 AD individuals. Linear mixed-effects models examined group differences as well as associations between baseline and longitudinal changes in ADI, CSF or PET biomarkers and clinical outcomes. Results derived from larger CSF (n=527) and PET (tau-PET: n=870; amyloid-PET: n=1581) data were also presented.

RESULTS: Compared to CN, the CI group exhibited significantly lower baseline ADI values and steeper longitudinal decline (p<10-⁶). Lower baseline ADI predicted faster cognitive and functional decline in the CI group (MMSE: p=0.03; CDR-SB: p<10-⁴), and longitudinal decreases in ADI were associated with worsening clinical outcomes (MMSE: p=0.001; CDR-SB: p<10-¹²). Compared to CSF and PET biomarkers, ADI demonstrated superior sensitivity in tracking disease progression and matched these biomarkers in predicting future cognitive and functional decline. Furthermore, decreases in ADI were significantly associated with declines in clinical outcomes; an association observed only with amyloid-PET, but not CSF biomarkers.

CONCLUSION: Axonal degeneration is an early and clinically meaningful feature of AD. ADI is a promising noninvasive biomarker for early detection, prognosis, and disease monitoring.

CLINICALTRIALS: gov NCT00106899.

FUNDING: This work was supported by the National Institute on Aging IRP.},
}

@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 {pmid41307506,
year = {2025},
author = {Fishman, A and Grinin, P and Riljak, V},
title = {The (un-)Social Brain in Isolation.},
journal = {Physiological research},
volume = {74},
number = {5},
pages = {711-727},
pmid = {41307506},
issn = {1802-9973},
mesh = {Humans ; *Social Isolation/psychology ; *Brain/physiology/physiopathology ; Animals ; *COVID-19/psychology ; *Social Behavior ; *Stress, Psychological/psychology ; },
abstract = {The Social Brain is a distributed network of neuroanatomical regions and neurochemical systems that underpins the human capacity for social cognition, empathy, and interpersonal behavior. Social isolation (SI), defined as the objective reduction in social interaction, poses a significant threat to the integrity of this system. In this review, we synthesize evidence from human and animal studies to elucidate the biological, cognitive, and behavioral consequences of SI on the social brain. We describe how SI acts as a chronic stressor, disrupting structural connectivity, and altering neurotransmitter systems critical for social cognition. These disruptions manifest in altered social behavior, mentalization processes, and emotional reactivity, significantly contributing to increased vulnerability to psychiatric and neurodegenerative disorders, including depression, schizophrenia, substance use disorders, and Alzheimer's disease. Converging findings from studies of evolutionarily conserved mechanisms in rodent and primate models demonstrate that SI compromises neurodevelopment, attenuates neuroplasticity, and triggers maladaptive stress responses, highlighting that social deprivation has profound neurobiological and behavioral consequences that greatly overlap with the pathophysiological changes seen in neuropsychiatric disorders. Furthermore, we explore the role of indirect stressors resulting from SI such as touch deprivation and digital-era social disconnection as contemporary amplifiers of SI's neurobiological impact. In light of public health challenges such as the COVID-19 pandemic, we propose that SI should be recognized not only as a psychosocial condition but as a modifiable risk factor with transdiagnostic significance across psychiatry, neurology, and preventive medicine. Addressing SI through targeted interventions and policy measures is essential for promoting mental resilience and well-being. Key words Chronic Stress " Loneliness " Social Cognition " Socialization " Social Stress.},
}

Humans
*Social Isolation/psychology
*Brain/physiology/physiopathology
Animals
*COVID-19/psychology
*Social Behavior
*Stress, Psychological/psychology

@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 {pmid41307432,
year = {2025},
author = {Nemr, MTM and Elshaier, YAAM and Ewieda, SY and Abdelaziz, MA},
title = {Pharmaceutical applications of cyclopropyl containing scaffolds: a review on recent updates.},
journal = {Future medicinal chemistry},
volume = {},
number = {},
pages = {1-10},
doi = {10.1080/17568919.2025.2594969},
pmid = {41307432},
issn = {1756-8927},
abstract = {Carbocycles have been widely employed in the development of pharmaceutically active scaffolds. Cyclopropane has attracted significant attention from researchers due to its unique chemical properties among carbocycles. Subsequently, this review will focus on cyclopropane-containing pharmaceutical drug products that have been approved by the FDA (Food and Drug Administration) and are used to treat a wide variety of medical conditions. In addition to the synthesis of the cyclopropyl moiety through various chemical reactions, such as the Corey-Chaykovsky reaction and the Simmons-Smith reaction. Several cyclopropane-containing pharmaceutical drugs have been reported to exert significant anti-coagulant effects. Additionally, they also exhibit inhibitory activity against MET, a receptor tyrosine kinase, as well as vascular endothelial growth factor receptor 2 (VEGFR-2). Moreover, they showed cytotoxicity by inhibiting epidermal growth factor receptor (EGFR[L858R/T790M]). In addition to antidiabetic, anti-Alzheimer, antimalarial, antimicrobial, anti-convulsant and anti-depressant activities. Herein, we present the pharmaceutical applications of cyclopropane-containing derivatives, shedding light on the structure-activity relationship (SAR), along with some commonly reported methods for their synthesis.},
}

@article {pmid41307255,
year = {2025},
author = {Hu, H and Li, H and Chen, Y and Zhou, J and Chen, J and Tang, Q and Chen, X and Jiang, J and Sun, M and Jia, D and Xie, W and Long, C and Yang, L},
title = {Molecular pathways underlying amyloid precursor protein-mediated regulation of adult-born neurons.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRR-D-25-00175},
pmid = {41307255},
issn = {1673-5374},
abstract = {Cleavage of amyloid precursor protein (APP) produces toxic amyloid-beta peptides, which play a critical role in the pathogenesis of Alzheimer's disease. Neuronal loss is a key feature of Alzheimer's disease. Despite the importance of APP in the proliferation of neural progenitors and the survival of adult-born granule cells in the dentate gyrus, little is known about the effect of APP deficiency on neuronal electrophysiological activities and the survival of newly born neurons. Utilizing whole-cell patch-clamp recording in combination with retroviral labeling and immunofluorescent staining in Alzheimer's disease model mice with App knockout (App-/-), we show that APP deficiency increased the number of adult-born granule cells at 4 weeks post-injection, but did not affect their intrinsic excitability or miniature current activity. In contrast, at 10 weeks post-injection, adult-born granule cells showed increased abundance and intrinsic excitability that were associated with abnormal dendritic morphology, increased miniature excitatory- and inhibitory-synaptic transmission, and decreased potassium-chloride-cotransporter 2 expression. Compared with adult-born granule cells at 10 week post-injection, mature granule cells exhibited decreased intrinsic excitability and potassium-chloride-cotransporter 2 expression alongside increased apoptosis in App-/- mice. Additionally, although App-/-mice showed abnormal freezing behavior and elevated mature granule cell activation during contextual fear conditioning, adult-born granule cells were not recruited in either App-/- or wild-type control mice. Taken together, these findings suggest that APP is required for adult-born granule cell maturation and that APP deficiency induces excitotoxicity in adult-born granule cells at 10 weeks post-injection, promoting subsequent apoptosis of mature granule cells.},
}

@article {pmid41307250,
year = {2025},
author = {Saieva, S and Scaduto, P and Fracassi, A and Guptarak, J and Zhang, WR and Johnson, K and Jupiter, DC and Marcatti, M and Zolochevska, O and Taglialatela, G and Micci, MA},
title = {Hippocampal neural stem cell-derived extracellular vesicles modulate microglia to promote resilience against tau oligomers.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRR-D-25-00195},
pmid = {41307250},
issn = {1673-5374},
abstract = {Neural stem cells and adult hippocampal neurogenesis modulate synaptic plasticity and cognitive function. Neural stem cells secrete extracellular vesicles - microvesicles carrying biomolecular cargos - that modulate the function of other cells and contribute to homeostasis and plasticity in the central nervous system. Alzheimer's disease is marked by a reduction of neural stem cells in the hippocampus dentate gyrus. While increased neural stem cells often correlate with better learning and memory, neurogenesis alone does not always preserve these processes, indicating that other mechanisms involving neural stem cells support memory. It has been shown that intracerebroventricular delivery of neural stem cell-derived small extracellular vesicles in wild-type mice reduces cognitive decline and toxic oligomer binding to synapses. We hypothesize that adequate neural stem cell numbers support neural stem cell-derived small extracellular vesicles protection of synapses against Alzheimer's disease toxic oligomers. Here, we show that elements of immune response in the central nervous system, particularly microglia, may contribute to this protective effect. Specifically, fluorescent-labeled small extracellular vesicles injected into wildtype mice brains were taken up by microglia, with only neural stem cell-derived small extracellular vesicles causing increased microglial activation, indicated by CD68 immunostaining. RNA-sequencing data showed selective activation of immune pathways in microglia by neural stem cell-derived small extracellular vesicles, leading to greater activation and higher Tau uptake 24 hours post-neural stem cell-derived small extracellular vesicle administration. Single-nuclei RNAsequencing of hippocampal microglia gene revealed modulation related to lysosomal activity, supporting neural stem cell-derived small extracellular vesicleinduced neuroprotection via microglia. This study uncovers a novel mechanism through which neural stem cell-derived small extracellular vesicles enhance microglial activity and provide neuroprotection in the hippocampus. Our data demonstrates that neural stem cell-derived small extracellular vesicle uptake by microglia leads to increased microglial activation and improved uptake of Tau oligomers by microglia, suggesting that neural stem cell-derived small extracellular vesicles may prime microglia for a more effective immune response. These results support the hypothesis that neural stem cell-derived small extracellular vesicle-induced modulation of microglial function is crucial for preserving neuronal integrity and mitigating neurodegenerative processes. By elucidating the interactions between neural stem cell-derived small extracellular vesicles and microglia, our study opens new avenues for developing therapeutic strategies aimed at boosting microglial function and addressing neurodegenerative diseases such as Alzheimer's disease.},
}