bluuebunny/crossref_metadata_2025_split huggingface dataset:
Develop a vascularized neuroimmune organoid model for studying sporadic Alzheimer’s disease
Authors: Xu Ranjie , Ji Yanru 
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD) is the leading cause of dementia, affecting 50 million people globally. Current AD animal models mainly focus on familial or inherited AD. These models often carry the APP and PSEN gene mutations from familial AD patients, or introduce microtubule‐associated protein tau (MAPT) mutations, which can cause frontotemporal dementia but are not linked to AD. Notably, there are significant species differences between humans and animals, and most AD therapeutics that have shown success in animal models have failed in clinical, highlighting the development of more translational human‐centric models for studying AD, particularly sporadic AD.MethodIn the current study, we developed a human‐induced pluripotent stem cell‐based vascularized neuroimmune organoids that contain multiple cell types in the human brain, including neurons, microglia, astrocytes, and blood vessels. We further challenge brain organoids with human AD postmortem brain tissues‐derived extracts to induce AD pathologies for studying sporadic AD. Finally, we applied this new model to test the effect of AD immunotherapy, such as Lecanemab.ResultAD brain extracts that contain pathological seeds, such as amyloid and tau, successfully induce multiple AD pathologies in neuro‐immune organoids, including 6E10+Aβ plagues, AT8+tau tangles, as well as neuroinflammation.ConclusionThe neuroimmune organoid model provides a unique opportunity to model sporadic AD in a human cell setting. This innovative model also facilitates AD drug screening, particularly for testing AD immunotherapy, such as antibody‐based AD treatment.
VEGF and ICAM5 Levels in Alzheimer’s Disease and Cognitively Healthy Aging
Authors: Nouh Claire Delpirou , Abiose Olamide , Wyss‐Coray Tony , Henderson Victor W , Sha Sharon J , Yutsis Maya , Mormino Elizabeth , Younes Kyan 
Published: January 2025

AbstractBackgroundVascular dysfunction, blood‐brain barrier (BBB) dysregulation, and neuroinflammation are thought to participate in Alzheimer`s disease (AD) pathogenesis, though the mechanism is poorly understood. Among pathways of interest, AD pathology appears to affect vascular endothelial growth factor‐A (VEGFA) signaling in a bidirectional manner. Higher VEGF levels are thought to have a protective role and slow cognitive decline. Neuronal intracellular adhesion molecules (ICAMs) may also be a marker of BBB permeability. ICAMs participate in the immune‐nervous system interactions, synaptic plasticity, and cognition.MethodWe used the SomaLogic platform for cerebrospinal fluid (CSF) proteome profiling to investigate the levels of ICAM 1, 2, 3, 5 and VEGFA as markers of vascular dysfunction and neuroinflammation in 83 participants from the Stanford Alzheimer Disease Research Center cohort (54 cognitively unimpaired healthy controls (HC) and 29 with mild cognitive impairment or dementia due to AD). All samples were blinded for analysis. Montreal Cognitive Assessment (MoCA) was used as a measure of global cognition. ANOVA compared the levels of biomarkers in diagnostic groups. Linear regression and interaction terms of group (AD vs HC) by biomarker levels were used to investigate the effect on global cognition.ResultICAM5 and VEGFA were significantly associated with cognition in our cohort. Both ICAM5 and VEGFA levels were lower in AD compared to HC (Figure 1). Interaction terms of diagnosis by ICAM5 were significant on MoCA (b = ‐59.29, p‐value < .0001), and of diagnosis by VEGFA were also significant on MoCA (b = ‐134.8, p:0.00027), indicating a divergent role for these biomarkers in AD vs. HC (Figure 2). Other ICAMs were not significantly associated with cognition in our cohort.ConclusionVEGFA and ICAM5 may play an important and dynamic role in AD. More research is needed to understand the interplay between ICAM5 and VEGF and their relationship with AD.References: Tao QQ et al. Aging Dis. 2022; Tubi MA et al. Neurobiol Aging. 2021; Petrelis AM et al. Aging (Albany NY). 2022; Yuan L et al. Aging Dis. 2017; Hino H et al. Brain Res. 1997; Yang H. Comp Funct Genomics. 2012; Birkner K et al. Front Neurol. 2019
Differential Association of Follicle‐Stimulating Hormone and Estrogen with Disease Severity and Cerebral Amyloid Deposition in Alzheimer’s Disease Spectrum
Authors: Wang Sheng‐Min , Jeong Chaiho , Um Yoo Hyun , Kang Dong Woo , Kim Sunghwan , Lee Chang Uk , Baek Ki‐Hyun , Lim Hyun Kook 
Published: January 2025

AbstractBackgroundWomen’s elevated risk of Alzheimer’s disease (AD) compared to men remains unclear, with gonadal hormones proposed as potential contributors. This study aimed to explore the association between follicle‐stimulating hormone (FSH), estradiol (E2), neuropsychological AD stages, and cerebral Aβ deposition.MethodsA total of 679 subjects were included in the study (N = 198 for cognitively normal (CN), N = 373 for mild cognitive impairment (MCI), and N = 108 for AD dementia groups). The inclusion criteria for all subjects were: (1) female sex, (2) age ≥ 55 years, (3) menopause defined as a minimum of 12 months passed since the last menstruation. Amyloid‐PET was conducted using 18F‐flutemetamol (18F‐FMM).ResultResults revealed significant differences in serum FSH levels among CN, MCI, and AD dementia groups (P < 0.001 for ANOVA), persisting after adjusting for age (P < 0.01 for ANCOVA). Post‐hoc analysis indicated higher FSH levels in the AD dementia group compared to MCI and CN groups, with no significant FSH differences between CN and MCI (Figure 1). Conversely, serum E2 levels showed no group differences (P = 0.076 for ANOVA), remaining statistically insignificant after age adjustment (P > 0.1 for ANCOVA). Correlation analysis demonstrated a negative association between FSH levels and CERAD‐K total score, including all sub‐measures except for constructional praxis. No significant associations were found between E2 levels and neuropsychological profiles. In the subset of 311 participants undergoing 18F‐FMM PET analysis, the A‐PET+ group exhibited higher FSH levels than A‐PET‐ group, while E2 levels did not differ (Figure 2). Positive correlations were observed between FSH levels and global and regional SUVR in the PCC/PC, frontal lobe, parietal lobe, and lateral temporal lobe (Figure 4). However, E2 levels showed no significant association with cerebral Aβ deposition.ConclusionThis study provides insights into the link between FSH, neuropsychological AD stages, and cerebral Aβ deposition in post‐menopausal women, highlighting FSH’s potential role as a biomarker. In contrast, such associations were not observed for E2. Further research is needed to unravel the underlying mechanisms and explore therapeutic avenues targeting hormonal pathways in AD.
Improving the global understanding of CADASIL‐ a monogenic cause of vascular dementia
Authors: Saks Danit G , Sachdev Perminder S. , Group AusCADASIL Study ,   the Global CADASIL Consortium (GCC)
Published: January 2025

AbstractBackgroundCerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a rare, hereditary cerebrovascular disease which causes stroke, complex migraine, and cognitive impairment. Given its monogenic nature, CADASIL is considered a ‘pure’ model of small vessel disease and vascular dementia. CADASIL is caused by NOTCH3 pathogenic variants with a broad resulting phenotypic spectrum. There are few CADASIL cohort studies worldwide, often with small or moderate samples, such that any study protocol variation limits the comparability of conclusions across populations. Our recently established Global CADASIL Consortium (GCC) will collate current research and develop guidelines for harmonised protocols and minimum datasets. Further, we have begun the first Australian cohort study of CADASIL, AusCADASIL, to determine the phenotypic presentation, progression, and pathogenic variants in this population.MethodLiterature search, publicising at the 2023 VASCOG conference, and chain‐referrals were used to identify CADASIL researchers and experts who may be interested in contributing to the global collaborative effort. Study meta‐data sharing is ongoing including demographics, clinical, genetic, and imaging outcomes.AusCADASIL will include 150 participants with genetically‐confirmed CADASIL, family history of CADASIL or suspected CADASIL symptoms, and 150 NOTCH3‐negative controls; to be assessed at six main sites. Participants will complete a comprehensive medical, neuropsychological, neurological, ocular, blood biomarker and genetic assessment, including annual follow‐up for 4 years to monitor progression. Data from this cohort will contribute to the international consortium.ResultThe GCC, comprised of 75 individuals from 18 countries, has begun by sharing meta‐data from 10 cohorts based in Australia, East Asia, Netherlands, USA, Spain, France, United Kingdom, and Finland with recruited sample sizes ranging from 20‐520 individuals, and discussing development of working groups. Recruitment for AusCADASIL opened in November 2023 and assessments will begin in early 2024.ConclusionThere is increased global interest in CADASIL as a model for small vessel disease and vascular dementia. This recently established international body is committed to improving the understanding of CADASIL, harmonising assessment protocols and pooling data for larger analyses of biomarkers. AusCADASIL is the first Australian cohort study of CADASIL and will contribute to international efforts.
TMEM106B C‐terminal fragments drive a distinct neurodegenerative proteinopathy in C. elegans.
Authors: Kraemer Brian C. , Riordan Ruben 
Published: January 2025

AbstractBackgroundGenetic variation of lysosomal protein, transmembrane protein 106B (TMEM106B) has long been known as a risk factor for a diverse range of neurodegenerative disorders, especially FTLD with progranulin (GRN) haplo‐insufficiency, though the mechanisms involved are not yet understood. Recently, through advances in cryo‐electron microscopy (cryo‐EM), aggregates of the C‐Terminal domain of TMEM106B (TMEM CT) were shown to make up previously unidentifiable protein aggregates in the brains of human FTLD, AD, progressive supranuclear palsy (PSP), and dementia with Lewy Bodies (DLB) patients.MethodsTo determine the TMEM CT aggregation propensity and neurodegenerative potential, we generated a new transgenic C. elegans proteinopathy model pan‐neuronally expressing the TMEM CT fragment constituting the fibrillar core in FTLD‐TDP cases.ResultsWe found that C. elegans pan‐neuronal expression of TMEM CT causes neuronal dysfunction as evidenced by behavioral analysis. TMEM c‐terminal fragments accumulate as detergent insoluble material. Behavioral dysfunction was accompanied by neurodegeneration as illustrated by loss of GABAergic neurons. To investigate the mechanisms driving TMEM106B proteinopathy, we aimed to explore the impact of GRN loss on the neurodegenerative effect of TMEM CT expression. To this end, we generated TMEM CT expressing C. elegans with PRGN loss of function. We found that loss of PGRN did not alter TMEM phenotypes confirming PGRN loss of function is upstream of TMEM aggregation. We also observed TMEM neurodegenerative phenotypes exhibit a distinct set of genetic modifiers as strong suppressors of tauopathy such as spop‐1, sut‐2 sut‐6 show only modest modification of TMEM proteinopathy.ConclusionsTaken together, our data suggest expression of TMEM CT in C. elegans neurons provides a useful model for the functional characterization of TMEM106B proteinopathy in neurodegenerative disease. Comparison with other proteinopathy models will inform potential disease mechanisms.
Accuracy of intact performance on measures of odor identification, global cognition, and amyloid imaging for identifying lack of cognitive decline and dementia in the Mayo Clinic Study of Aging cohort
Authors: Motter Jeffrey N , Lee Seonjoo , Knopman David S. , Vassilaki Maria , Devanand Davangere 
Published: January 2025

AbstractBackgroundPrevious studies have linked impaired odor identification and global cognition with increased risk of cognitive decline and transition to dementia. However, the reverse question remains: if individuals have intact performance on these measures, are they at reduced risk for transition? We aimed to examine the accuracy of intact odor identification and global cognition for identifying lack of transition to dementia/cognitive decline using the population‐based Mayo Clinic Study of Aging and compare their accuracy against and in combination with amyloid PET (Positron Emission Tomography).Methodn = 647 participants age≥55 without dementia completed at baseline the Brief Smell Identification Test (BSIT; ‘Intact’ = 9‐12), Blessed Information‐Memory‐Concentration Test (BIMCT; ‘Intact’ = 18‐20,), and amyloid PET (‘Normal/Intact’ SUVR<1.48). We calculated sensitivity, specificity, positive predictive value, and negative predictive value for these measures, with “lack of transition to dementia” as the gold standard/target. “Lack of cognitive decline” (cognitively unimpaired to mild cognitive impairment [MCI]; cognitively unimpaired to dementia; or MCI to dementia) was a secondary target.Result94.7% of participants (613/647) did not transition to dementia and 84.2% (545/647) did not cognitively decline over 11.25‐year‐follow‐up. The combination of intact BSIT+BIMCT had high rates of lack of transition to dementia (98.3%, 355/361) and lack of cognitive decline (93.1%, 336/361). This combination yielded mixed sensitivity (0.579) and specificity (0.824) though had high positive predictive value (0.983) for identifying lack of transition to dementia. Intact amyloid PET alone exhibited comparable rates of lack of transition to dementia (99.0%, 418/423) and lack of cognitive decline (92.4%, 391/423). When evaluated conjointly, the combination of all three intact measures also had mixed sensitivity (0.421) and specificity (0.962) though higher positive predictive value (PPV = 0.996) for lack of transition to dementia. 99.6% (258/259) of participants with intact/normal status on all three did not transition to dementia and 96.5% (250/259) did not cognitively decline.ConclusionThis replicates prior reports that intact olfaction/global cognition have strong utility for identifying individuals unlikely to develop MCI/dementia. Intact/normal amyloid PET further enhances the positive predictive value. Clinically, identifying individuals at low risk of transition can shorten diagnostic workups, reduce need for early follow‐up visits, and screen patients in‐or‐out of clinical trials.
Voice Problems and Depression: Findings from the 2022 National Health Interview Survey
Authors: Hong Ickpyo , LEE HOKYUNG 
Published: January 2025

AbstractBackgroundIn contemporary society, essential for quality of life and professional success, is impacted by voice problems affecting 3∼9% of the population. These issues, leading to significant health and economic burdens, can alter voice frequency and tone, impacting self‐esteem, social interactions, and professional outcomes. Voice problems are linked to social isolation and depression, a major emotional disorder causing lethargy and loss of hope. Studies, including the 2012 National Health Interview Survey, show higher depression rates in individuals with voice issues. Our study aimed to use the most recent national survey data and examine this link, and also provide insights for better treatment strategies.MethodThis study utilized the 2022 National Health Interview Survey to explore the relationship between voice problems and depression in U.S. adults. The independent variable is self‐reported voice problems, while the dependent variable is depression, measured using the PHQ‐8 questionnaire. Covariates included sex, age, race, education, income, comorbidities, body weight, and anxiety disorders. Propensity score matching techniques and multivariate logistic regression were used to control for selection bias between the comparison groups. Subgroup analysis investigated the link between the severity of voice problems and depression.ResultThe study found that 12.24% of U.S. adults reported voice problems in 2022. Demographics and health conditions significantly differed between those with and without voice problems. Depression was 1.6 times more likely in individuals with voice problems, and lower in men and non‐white ethnicities (OR = 1.655, 95% CI [1.495, 1.832]). After propensity score matching, covariates were balanced, confirming a consistent, significant association between voice problems and depression across various adjustment models. Subgroup analysis showed a stronger association of depression severity with voice problems severity and anxiety disorders, with women exhibiting a negative correlation(β = 0.89, p <.0001; β = ‐0.13, p <.0001).ConclusionThe study highlights a strong association between voice problems and increased depression risk, especially in women and those with anxiety disorders. These findings emphasize the importance of specialized intervention strategies to address these issues.
Exposure to melamine exacerbates D‐galactose‐induced aging‐type toxicity in neuronal SH‐SY5Y cells
Authors: Rai Nitish 
Published: January 2025

AbstractBackgroundVarious investigations have elucidated the impact of diet and environmental toxins on the aging process. Melamine (Mel) is a widely recognized and infamous food adulterant with documented toxicity in various organs, including the brain. Nevertheless, there is currently a dearth of reports on the neurotoxic effects of Mel in aging neurons. This study aims to fill this knowledge gap by exploring the in‐vitro neurotoxicity induced by Mel in a D‐galactose (DG) induced aging model, utilizing neuronal SH‐SY5Y cells.MethodIn this current investigation, the neuronal SH‐SY5Y cells underwent separate and combined treatments with D‐galactose (DG) and Melamine (Mel) to evaluate their neurotoxic potential. The assessment involved employing the MTT assay for cell viability and measuring neurite length. Additionally, we examined the activities of superoxide dismutase (SOD), catalase (CAT), and total antioxidant levels. Subsequent analyses included determining intracellular reactive oxygen species (ROS), mitochondrial membrane potential (MMP), and caspase‐3 (Casp3) activity.ResultWhen Melamine (Mel) and D‐galactose (DG) were co‐administered to neuronal SH‐SY5Y cells, a notable increase in cell death was observed compared to cells treated with DG or Mel individually, as well as untreated control cells. The co‐treated cells exhibited the most significant shrinkage in neurite length and the highest production of reactive oxygen species (ROS), indicating an exacerbated toxicity from Mel. Furthermore, the combined treatment (Mel + DG) led to a decrease in the activity of superoxide dismutase (SOD), catalase (CAT), and total antioxidants compared to cells treated with Mel or DG alone and untreated cells. Additionally, the co‐toxicity of Mel and DG significantly elevated the activity of caspase‐3 (Casp3) compared to all other groups, underscoring an enhanced apoptotic response.ConclusionThis study represents the initial exploration into the heightened neurotoxic potential of Melamine (Mel) within an aging model of neuronal SH‐SY5Y cells. These findings suggest that Mel consumption by the elderly could potentially contribute to elevated occurrences of neurodegenerative conditions such as Alzheimer’s disease and Parkinson’s disease.
A non‐canonical Receptor tyrosine kinase DDR2 resides inside the nuclear speckles and regulates alternative splicing in Alzheimer’s
Authors: Das Russa , Mukhopadhyay Debashis 
Published: January 2025

AbstractBackgroundReceptor Tyrosine kinase‐mediated signaling is indispensable for the cell’s normal functioning, the perturbation of which leads to disease conditions. The altered expression and activity of several Receptor Tyrosine kinases (RTKs) are known to regulate the pathophysiology of Alzheimer’s disease (AD). However, the mechanistic details remain illusive. Discoidin Domain Receptor 2 (DDR2) is a unique set of RTKs that gets significantly upregulated in an Alzheimer’s disease (AD) cell model and AD brain lysate.MethodThe AD cell model was prepared using SH‐SY5Y cells and treated with AICD and Aß for 48 hours and was checked for the activity and expression level of DDR2. The expression level of the collagens was also checked. Molecular docking studies were performed to predict the interaction between DDR2 and Amyloid beta. ICC followed by nuclear fractionation studies was performed to confirm the compartmental distribution of DDR2 in the AD model. Immunoprecipitation followed by mass‐spectrometry was done to confirm the interactors of DDR2 in AD.ResultThe mRNA and protein levels and activity of DDR2 were significantly upregulated in the AD cell model. There were no significant changes in the mRNA expression level of collagens. Molecular docking followed by ICC studies confirms the interaction between DDR2 and amyloid beta. Again, for the first time, we showed that DDR2 translocates to the nucleus in an untreated condition in SH‐SY5Y cells, and also the DDR2 level increases in AD nucleus compared to control using ICC and nuclear fractionation. Moreover, we observed that DDR2 forms a punctate structure inside the nucleus that strongly colocalizes with SRSF2 a nuclear speckle protein. Immunoprecipitation of DDR2 followed by Mass spectrometry (MS) in the AD cell model revealed some important proteins like HNRNPH1, HNRNPU, PCBP2, and SRSF7 as binding partners of DDR2, implicating a role of DDR2 in mRNA splicing.ConclusionDDR2 which is a receptor tyrosine kinase, in the absence of its endogenous ligand collagen gets activated in AD by interacting with amyloid beta and translocates to the nucleus. DDR2 resides inside the nuclear speckles, and interacts with several splicing factors, thereby regulating alternative splicing in AD.
Uncovering the association between dysphagia and depression: Insights from the 2022 National Health Interview Survey
Authors: Yoo Sanghee , Hong Ickpyo 
Published: January 2025

AbstractBackgroundDysphagia can increase fear of swallowing, reduce self‐esteem, and hinder social relationships. Such factors can also increase anxiety and degrade the quality of life. This study aimed to elucidate the association between dysphagia and depressive symptoms.MethodThis study conducted an assessment of 26,810 U.S. adults using the 2022 National Health Interview Survey (NHIS) database. Multiple regression analysis and five different propensity score matching approaches were used to account for sex, race/ethnicity, educational attainment, household income, number of comorbid chronic diseases, and presence of anxiety disorder.ResultUtilizing the 2022 NHIS database, 26,810 American adults were assessed. Of the weighted population demographics, 51.88% reported having dysphagia, with 43.64% being females and an average age of 46.17 (SD 0.22). The study findings revealed that individuals reporting dysphagia had an elevated likelihood of presenting depressive symptoms (OR = 1.875, p < .0001). Several factors influencing depressive symptoms were identified, including sex, race, educational attainment, household income, the number of accompanying chronic diseases, and the presence of an anxiety disorder. Females exhibited a higher likelihood of depression (OR = 1.441; 95%CI 1.354, 1.533) compared to males. Individuals with educational levels of ‘some college’ or higher demonstrated elevated odds ratios for depressive symptoms relative to those who did not complete high school (OR = 1.141; 95%CI 1.018, 1.279). The presence of two‐plus chronic diseases significantly upped depression risks (OR = 1.902; 95%CI 1.725, 2.097), with anxiety disorders further amplifying this (OR = 5.147; 95%CI 4.676, 5.664).ConclusionThis study demonstrated the intricate interplay between dysphagia and various demographic and health factors, emphasizing the critical need for individualized management strategies for depression in patients with dysphagia.