bluuebunny/crossref_metadata_2025_split huggingface dataset:
Functional brain network organization supports cognitive function in patients with Alzheimer's Disease‐related pathological burden and brain atrophy
Authors: Zhang Ziwei , Chan Micaela , Winter‐Nelson Ezra , Wig Gagan S 
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD) is defined by the accumulation of Aß plaques and tau neurofibrillary tangles. The consequences of these pathologies include neurodegeneration and cognitive dysfunction. However, the process by which AD pathologies leads to cognitive impairment remains unclear. Some individuals can harbor pathological burden yet be cognitively unimpaired; these observations have led to ideas about cognitive reserve (Stern, Lancet, 2012). Dominant models of AD biomarkers do not include direct measures of brain function. To address this gap, we tested whether resting‐state brain system segregation explains discrepancies between AD‐related pathology, structural atrophy, and cognitive function. System segregation changes across the adult lifespan, is stratified in relation to life course exposures, and relates to cognitive function (Wig, Trends in Cognitive Sciences, 2017).MethodParticipants were recruited through the Alzheimer’s Disease Neuroimaging Initiative. Cognitive impairment was quantified using clinical dementia rating (CDR). The participant group included 184 healthy (CDR=0) adults, 101 very mild dementia (CDR=0.5), 24 mild dementia (CDR=1) and 2 moderate dementia (CDR=2) patients (age range: 55–96 years). Functional brain networks were generated using resting‐state fMRI time series. Network edges were defined as correlations between time series of each pair of nodes. Brain system segregation was calculated to quantify functional brain network organization for each participant (Chan et al., PNAS, 2014).ResultMultiple linear regression analyses were used to test whether Aß and tau relate to brain system segregation, with age, gender, education, and head motion included as covariates. Neither Aß nor tau burden was associated with brain system segregation (Aß: p=0.45; tau: p=0.55). Among individuals exhibiting positive pathological burden (either Aß, tau, or both) based on cut‐off values, individuals with higher system segregation were less cognitively impaired (Aß+: p=0.007; tau+: p=0.021; Aß and tau+: p=0.03). Finally, system segregation explained unique variance with respect to CDR status over and above Aß, tau, and cortical thickness. Brain system segregation was negatively related to CDR status (p=0.003), while accounting for these other factors.ConclusionFunctional brain network organization supports observations of cognitive reserve, and explains unique variance with respect to AD‐related cognitive impairment independent of AD‐related pathology and neurodegeneration.
Benzofuroisoquinoline derivatives reverse amyloidogenesis and amyloid‐associated memory impairments in acute and transgenic mouse models of Alzheimer’s disease
Authors: Park InWook , Park Sohui , Jeon Hanna , Kim Kyeonghwan , Yoon Soljee , Shin Jisu , Kim Hye Yun , Kim Ikyon , Kim YoungSoo 
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD) is predominantly caused by the aggregation of amyloid‐β (Aβ) peptides into neurotoxic plaques. Current therapeutic approaches using monoclonal antibodies, like aducanumab and lecanemab, have shown promise in reversing Aβ aggregation. However, these treatments are expensive and challenging to administer. Small molecules offer a more accessible alternative but face specificity hurdles. Our study explores a library of hybrid compounds, integrating structures known to affect Aβ aggregation, to find potential small molecule therapeutics for AD.MethodWe utilized a thioflavin T (ThT) fluorescence assay to measure the inhibitory effects of YIAD compounds on Aβ aggregation. Compounds were tested at varying concentrations with preformed Aβ aggregates. For analysis of Aβ species post‐inhibition, SDS‐PAGE coupled with photocrosslinking (PICUP) and silver staining were employed. In vivo efficacy was assessed using an Aβ‐infused mouse model and a 5XFAD transgenic mouse model, with cognitive function measured by a Y‐maze test and Aβ plaque burden by thioflavin S (ThS) staining.ResultThT assays indicated that certain YIAD compounds significantly inhibited Aβ aggregation. SDS‐PAGE analyses confirmed changes in Aβ species distribution upon compound treatment. Aβ aggregate dissociation was demonstrated with ThT assays, indicating potential for plaque clearance. YIAD‐0405 and 0407 significantly improved spatial memory in the Y‐maze test and reduced plaque burden in 5XFAD mice, as evident from ThS staining.ConclusionOur findings suggest that YIAD compounds, specifically YIAD‐0405 and 0407, effectively inhibit and dissociate Aβ aggregates in vitro and in vivo. These compounds improve cognitive function and decrease plaque burden, positioning them as promising candidates for oral AD therapeutics. Further studies will explore their mechanistic pathways and long‐term efficacy in treating Alzheimer’s disease.
An autophagy adaptor TRIAD3A promotes tau fibrillation by phase separation
Authors: ZHOU JIECHAO 
Published: January 2025

AbstractBackgroundMultiple neurodegenerative diseases are characterized by aberrant proteinaceous accumulations of tau. The maintenance of tau proteostasis reportedly involves the clearance of insoluble tau aggregates by aggrephagy receptors. However, the precise molecular mechanisms underlying both tau fibril formation and degradation remain largely elusive.MethodWe conducted comprehensive investigations, employing both in vivo and in vitro methodologies, to analyze the phase separation of TRIAD3A. Leveraging biochemical assays alongside IHC‐IF and CLEM, identified TRIAD3A as an autophagy adaptor. Employing the TRIAD3A‐TurboID proximity labeling strategy, coupled with CoIP techniques in both in vivo and in vitro settings, we elucidated the binding of TRIAD3A to Tau. Furthermore, employing a tauopathy mouse model, and conducting colocalization studies in human Alzheimer’s disease (AD) brain tissue, we investigated the impact of TRIAD3A on tau homeostasis.ResultHere, we report an RBR‐type E3 ligase TRIAD3A functions as an autophagy adaptor for tau. TRIAD3A(RNF216) is an essential gene with mutations causing age‐progressive neurodegeneration. Our studies reveal that TRIAD3A E3 ligase catalyzes mixed K11/K63 polyubiquitin chains and self assembles into liquid‐liquid phase separated (LLPS) droplets. Tau is ubiquitinated and accumulates within TRIAD3A LLPS droplets and via LC3 interacting regions targets tau for autophagic degradation. Unexpectedly, tau sequestered within TRIAD3A droplets rapidly converts to fibrillar aggregates without the transitional liquid phase of tau. In vivo studies reveal TRIAD3A decreases the accumulation of phosphorylated tau in a tauopathy mouse model, and disease‐associated mutation of TRIAD3A increases accumulation of phosphorylated tau, exacerbates gliosis, and increases pathological tau spreading. In human Alzheimer’s disease brain, TRIAD3A colocalizes with tau amyloid in multiple histological forms suggesting a role in tau proteostasis.ConclusionTRIAD3A is the first autophagic adaptor that utilizes E3‐ligase and LLPS as a mechanism to capture tau, thus preventing pathologic tau aggregation and spread.
Effects of a subject‐led social participation program to improve social well‐being of senior citizens in the community
Authors: Kim Inhye , An Hyunseo , Yun Sohyeon , Shin Jiwon , Yang Hyun , Park Hae Yean 
Published: January 2025

AbstractBackgroundAs populations age, fostering the social participation of older adults is crucial to addressing issues like isolation. This study introduced a subject‐led social participation program to encourage independent engagement among older adults, utilizing a custom‐designed menu of activities. The program’s impact on social well‐being was assessed to explore its practical application and identify potential improvements.MethodThe program was evaluated using a single‐group pre‐post design from February to April 2024. Participants included seniors aged 65 or older from small to medium cities, engaging in social activities less than three times a week, with independent mobility and normal cognitive function. Twelve sessions, each lasting 60‐90 minutes, were conducted over six weeks. Social well‐being improvements were measured using various scales, including SPF‐IL, the Quality of Life Scale for the Elderly, and the UCLA Loneliness Scale 3rd edition. Program activities were categorized into social, rules, and honor activities, each involving planning and implementation phases based on discussions and using the social participation menu.ResultsFour seniors participated in the study. The program positively changed social well‐being, self‐efficacy, and loneliness. Post‐program interviews aligned subjective experiences with observed improvements, indicating effective social integration and continued participation benefits.ConclusionThe subject‐led program effectively enhances social well‐being, reduces loneliness, and increases self‐efficacy among older adults. Participants reported long‐lasting learning effects and a newfound sense of societal integration, suggesting the program could effectively engage older adults in traditionally perceived as youth‐oriented meaningful activities. However, the small sample size calls for further studies with more participants and a control group to confirm these findings and ensure broader applicability.
Deciphering the Role of Ubiquitination in Tauopathies
Authors: Vanparys Axelle A.T. , Zola Nathalie Kyalu Ngoie , Balty Clémence , Boyer Emilien , Vertommen Didier , Kienlen‐Campard Pascal , Hanseeuw Bernard J 
Published: January 2025

AbstractBackgroundTauopathies are defined as a group of heterogeneous neurodegenerative disorders, characterized by abnormal Tau protein accumulation in neurons and glial cells. The most common tauopathy is Alzheimer’s disease (AD), which is responsible for 70% of cases dementia. The development of tauopathies is a multistep process probably driven by changes in the post‐translational modifications (PTMs) of Tau. Unfortunately, for almost all these diseases, no accurate differential diagnostic methods are available which exacerbates the need of identifying biomarkers or treatments for tauopathies. In addition to providing a better understanding of the pathophysiology of tauopathies, the study of PTMs seems well suitable for these aims. According to the literature and previous results from the lab, ubiquitination appears promising to identify biomarkers allowing the differentiation of tauopathies and to treat these pathologies. Therefore, this project aims to evaluate the predictive value of ubiquitination dysregulation in the tauopathies, as a tool for diagnosis and a mechanism of tau aggregation.MethodTo achieve our goal, we first segregated the soluble and insoluble brain protein fractions from brain of subjects with specific tauopathies (AD, Pick’s disease, frontotemporal lobar degeneration and corticobasal degeneration) and healthy subjects. Tandem mass spectrometry (LC‐MS/MS) was used to identify all the proteins present in the insoluble fractions using DDA (data dependent acquisition), as well as in the soluble fraction enriched in ubiquitinated proteins. The post‐analysis was performed using Proteome Discoverer software and the statistical analyses were done in R.ResultThis analysis allows the identification of an imbalance in proteins ubiquitination in the insoluble fraction of tauopathies brains. Moreover, the imbalance provides ubiquitin hallmarks associated to specific tauopathies. Finally, we also investigated Tau ubiquitination profile in these fractions.ConclusionOur study suggests that ubiquitination may be dysregulated in tauopathies, in which ubiquitinated tau accumulates. This could arise either from impairment of tau clearance in autophagy/lysosomal compartments, or as a consequence of altered proteasome function, well‐described in AD. The dysregulation of ubiquitination appearing in tauopathies underscores the potentially significant role of this post‐translational modification in the development of these pathologies.
Long‐Term Assessment of Career Outcomes among US‐based Participants in a Novel AD/ADRD Clinical Trial Training Program: the IMPACT‐AD Experience
Authors: Mastrolorenzo Margaret D , Carrillo Maria C. , Sperling Reisa A , Petersen Ronald C. , Aisen Paul S. , Snyder Heather M , Grill Joshua D , Raman Rema 
Published: January 2025

AbstractBackgroundThe Institute on Methods and Protocols for Advancement of Clinical Trials in Alzheimer’s Disease and Alzheimer’s Disease Related Dementias (AD/ADRD) (IMPACT‐AD) is a novel multi‐disciplinary training program funded by the National Institute on Aging (NIA) and the Alzheimer’s Association for individuals seeking expertise in designing and conducting AD/ADRD trials. IMPACT‐AD offers a Professionals Track for investigators in a variety of trial roles and a Fellowship Track for future AD/ADRD clinical trial principal investigators.MethodTo evaluate long‐term training outcomes, alumni‐scholars from the 2020‐2022 courses (n = 109) were surveyed via REDCap in January 2024. Measured constructs encompassed alumni‐scholar retention in AD/ADRD trials, promotions received, project funding, and the status of the protocol developed during the course, including whether it had been funded, conducted, and published (Fellowship Track). Alumni‐scholars rated the extent to which the course facilitated their achievements (not at all, somewhat, very much).ResultOf the 63 (58%) of alumni‐scholars who responded (48% Professional Track, 69% Fellowship Track), 44 (70%) were female. 21 (33%) identified as African American/Black, Asian, Multiracial or of another race; 7 (11%) self‐identified as Hispanic/Latino ethnicity. 5 (8%) identified as LGBTQ+. 12 (19%) indicated being first in their families to attend college.Since program completion, 87% of survey participants maintained a career in ADRD clinical trials. A majority (63%) experienced a promotion or career advancement, with all indicating that IMPACT‐AD “somewhat” or “very much” contributed. Less than half of scholars (43%) had received project funding since IMPACT‐AD, but 74% of those had credited IMPACT‐AD at least somewhat for this achievement. Among the 34 Fellowship Track respondents, 15 (44%) indicated that the trial proposed at IMPACT‐AD had received funding, 14 (41%) reported its completion, and 5 (15%) had published its results. Nearly all respondents (%) reported assuming additional roles and responsibilities within their current title. In total, 92% of surveyed participants reported at least one positive change across all measured categories.ConclusionIMPACT‐AD is effectively fulfilling its goals of training, nurturing, and diversifying a next generation of AD/ADRD trialists.
KET‐MCI: An open‐label trial of single‐dose ketamine treatment to improve depression in mild cognitive impairment
Authors: Fremont Rachel , Karim Amelia , Feder Adriana , Naasan Georges , Murrough James , Berman Julia 
Published: January 2025

AbstractBackgroundThe U.S. Population is older today than it has ever been. It is estimated that 12‐18% of people over the age of 60 have mild cognitive impairment (MCI). 35‐85% of individuals with MCI have neuropsychiatric symptom with the prevalence of depression alone being between 25‐40%. Unfortunately, evidence suggests that traditional antidepressant medications may be less effective for individuals with MCI and depression (MCI‐D). Therefore, there is a need to develop novel effective treatments for depression in MCI.MethodThe primary goal of this open‐label clinical trial is to explore whether a single sub‐anesthetic (0.5 mg/kg) dose of intravenous (IV) ketamine, an N‐methyl‐D‐aspartate (NMDA) receptor blocker that has been shown to have a rapid and strong anti‐depressant effect in individuals with major depressive disorder, is safe and tolerable in individuals with MCI‐D. Participants receive a single infusion of ketamine with follow up 24 hours, 48 hours, 72 hours, 1 week, and 1 month after infusion. Other study outcomes include the Montgomery‐Asberg Depression Rating Scale (MADRS), the mini‐mental status exam (MMSE), blood‐based biomarkers, and neuroimaging.Result8 Individuals with MCI‐D have completed the single infusion, 5 have completed the study and 3 are in follow‐up. So far, no serious adverse events have been reported. Adverse events included transient hypertension during infusion, fall, anxiety, lightheadedness, brain fog, and headache. All participants completed the single infusion and no study participants have dropped out. 100% of participants responded to treatment, defined as 50% reduction in MADRS, at 24 hours (n = 8). Response rates at 1 week (n = 8) were 62% and at 1 month (n = 5) were 60%.ConclusionSub‐anesthetic IV ketamine appears to be safe and tolerable in individuals with MCI‐D and may improve depressive symptoms. Larger randomized controlled studies should be performed to evaluate the utility of this treatment in individuals with MCI‐D.
Multiomic Characterization of Male and Female Aging Brain in Aromatase Deficiency Mice at Single‐Cell Resolution
Authors: Potluri Tanvi , Rodriguez Guadalupe , Dong Hongxin , Zhao Hong , Bulun Serdar E 
Published: January 2025

AbstractBackgroundAging and the decline in sex steroid hormone (e.g., estrogen) are associated with a potential loss of its neuroprotective effects on the female brain. Aromatase, a pivotal enzyme in the synthesis of estradiol (E2), is highly expressed in various brain regions, notably the hippocampus. However, how estrogen regulates brain function and how dysregulation of estrogen signaling modulates the risk of Alzheimer’s disease are not well understood. Furthermore, the mechanisms through which E2 modulates brain cell‐type specific transcriptomic and epigenetic changes, particularly in the context of aging and susceptibility to Alzheimer’s disease, remain inadequately understood. Additionally, investigations into the effects of E2 on both male and female sexes are limited.MethodIn this study, we employed a brain‐specific aromatase knockout (bArKO) mouse model to examine the epigenetic and transcriptomic alterations in mouse brains characterized by E2 deficiency and aging. We performed single‐nucleus RNA sequencing (snRNA‐seq) and Assay for Transposase‐Accessible Chromatin with sequencing (snATAC‐seq) at the same cells from the hippocampus of ∼20‐month‐old male and female bArKO mice and their wild‐type (WT) littermate controls (n = 3/sex/genotype).ResultOverall, 77,200 nuclei were analyzed post quality control, annotating 32,285 genes. After dimension reduction, we obtained 23 clusters representing excitatory and inhibitory neurons, microglia, astrocytes, oligodendrocytes, oligodendrocyte precursor cells, ependymal cells, and perivascular macrophages. Four populations of Gad1
+ inhibitory neurons were observed: Sst
+, Vip1
+, Crispld1
+, and Cdh18
+. Conversely, eight populations of excitatory neurons were uncovered, with significant transcriptomic changes observed between WT and bArKO neurons. Pathway analysis revealed overrepresentation of dopamine secretion regulation and dendrite arborization in bArKO mice. Additionally, known sex‐specific genes were observed. Males predominantly expressed Eif2s3y and Uty while female mice showed higher expression of Tsix, Xist, and Jpx.ConclusionIn summary, our study sheds light on the molecular and cellular alterations occurring in the hippocampus of aging mice with E2 deficiency, particularly focusing on the role of aromatase in modulating brain function. The identification of distinct neuronal populations and differential gene expression patterns between WT and bArKO mice highlights the complexity of E2‐mediated neuroprotection and its relevance in both sexes.
A Comprehensive Neurological Study on the Relationship Between Prolactinoma and Alzheimer’s Disease
Authors: Zid Mohamed Khaled Ali Mohamed Ali , El‐Satar Youssef M. Abd , Shahin Arwa Ayman Nagah Ahmed 
Published: January 2025

AbstractBackgroundAlthough most pituitary tumors are benign, functioning pituitary tumors are dangerous as they produce and deteriorate the endocrine hormones. Prolactinomas are one of these tumors that arise from lactotroph cells of the anterior pituitary, and they're about 40% of all pituitary adenomas. They secrete high levels of prolactin, which are normally inhibited by dopamine. So, in cases of excess prolactin secretion in prolactinoma, dopamine levels will be elevated as negative feedback. Also, the dopamine system plays a role in cognitive functions and Alzheimer’s disease (AD).MethodWe searched relevant articles through December 2023 in those electronic databases: PubMed, Embase, Web of Science, PsycArticles, MEDLINE, PsycINFO, and the Cochrane Central Register of Controlled Trials; and additional searches for ongoing trials through ClinicalTrials.gov, World Health Organization International Clinical Trials Registry Platform.ResultProlactinomas are found most frequently, with an estimated incidence rate of 10/100,000 person‐years in women of reproductive age. As prolactinomas are the leading pathological case of increasing levels of prolactin, prolactin at first self‐regulates by increasing dopamine release. But in high prolactin states, central dopaminergic neurons become refractory to prolactin, which won’t increase the dopamine level and quite the opposite the dopamine levels would decrease. Some findings suggest that reduced levels of dopamine are associated with AD. Therefore, higher levels of synaptic dopamine would delay the onset of AD. But lately, it has increased the risk of AD.ConclusionThese results may suggest clarifying the relationship between dopamine levels in prolactinoma and the incidence of AD. So patients who are suffering from prolactinomas will have a lower risk factor of getting AD at first. But if they haven’t been treated by dopamine agonists or even surgically removal of the tumor, there will be a higher expectation for the occurrence of AD.
Efficacy of Emerging Digital Screening Tools in Detecting Cognitive Impairment Among Low Educational Elderly in Western China: A Community‐Based Study
Authors: zhang xiaonan , li yang 
Published: January 2025

AbstractBackgroundThis study investigated the efficacy of emerging digital screening tools for detecting cognitive impairment (CI) in a large community of elderly individuals with lower educational backgrounds.MethodThis community‐based cohort study included 1083 participants (age≥65 years), 337 of whom were diagnosed with CI (64.1%≤6 years). We utilized three types of tools: traditional tests (AD8 and MMSE), a digitally improved Mini‐Cog scale, and digital behavioral tools (gait and eye movement tests). We construct LightGBM machine learning models of different digital screening tools and their combinations and evaluate their performance. The correlation between each model’s top 10 key features and cognitive domain scores was analyzed.ResultEmerging digital screening tools [AUC: eye movement (0.89)> digital Mini‐Cog (0.86)> gait (0.83)] showed promising efficacy in distinguishing CI from NC. The AUC of combination 1(digital Mini‐Cog & gait) was 0.89, and that of combination 2(eye movement & gait) was improved to 0.93. Combination 3 (eye movement & digital Mini‐Cog) achieved the highest classification efficacy (AUC = 0.96), with accuracy, sensitivity, and specificity all above 83%. In the subgroup analysis (≤6 years), the AUC for eye movement in identifying CI decreased to 0.74. Different behavioral features reflected varying impairments across cognitive domains.ConclusionEmerging digital technologies offer objective, accurate, and efficient alternatives for CI detection, and are anticipated to replace traditional tests in community screenings. But the applicability of these tools in lower educational groups (≤6 years) should be cautious.