bluuebunny/crossref_metadata_2025_split huggingface dataset:
APOE4 impairs Microglia ‐ Astrocyte Crosstalk in Alzheimer Disease
Authors: Kleemann Kilian , Rosenzweig Neta , Yin Zhuoran , Zhang Xiaoming , Brandao Wesley N , Margeta Milica , Schroeder Caitlin M , Silveira Sebastian , Gauthier Christian , Mallah Dania , Pitts Kristen , Herron Shawn , Shorey Hannah , Aronchik Michael , Wang Chao , Jain Nimansha , Bao Xin , Brouwer Nieske , Baufeld Caroline , Krasemann Susanne , Eggen Bart , Clish Clary , Tanzi Rudolph E. , Madore Charlotte , Wakelin Sam , Rhee Jared , Cheng Yiran , Barry Jen‐Li , Yung Anthony , Gerrits Emma , Deik Amy , Tenen Daniel G. , Santander Nicolas G. , Ikezu Tsuneya , McKinsey Gabriel L. , Sheppard Dean , Arnold Thomas D. , Durao Ana , Holtzman David M. , Butovsky Oleg 
Published: December 2023

AbstractBackgroundAPOE4 is the major genetic risk factor for late‐onset Alzheimer Disease (AD). APOE signaling is critical for the transition of homeostatic microglia to the neurodegenerative phenotype (MGnD). The intrinsic role of APOE4 in microglia and its contribution to AD is unclear.Method
Generation of Cx3cr1‐CREERT2 mice crossed to APOE‐KI(APOE3 and APOE4)fl/fl injected with labeled apoptotic neurons (MGnD‐Pardigm) on WT or APP/PS1 background. Microglia and astrocytes were isolated and sequenced using either bulk RNA‐seq (MGnD‐Paradigm) or single‐cell RNA‐seq (APP/PS1). Crosstalk between cells was determined using the NichenetR database and validated using 1) Recombinant Lgals3 intracranial injection into APP/PS1 mice and 2) Adoptive transfer of microglia, from APOE3‐KI, APOE4‐KI and APOE4‐cKO mice challenged with labeled apoptotic neurons, into WT mice and isolation of astrocytes.ResultExpression of APOE4 in microglia impaired MGnD‐transition in response to neurodegeneration and in APP/PS1 mice. Conditional deletion of APOE4 in microglia restored MGnD phenotype and reduced plaque pathology. Furthermore, increased astrocytic recruitment towards plaques and their activation by increased Gfap and Serpina3n expression was identified. Microglial Lgals3 was determined as critical crosstalk effector to promote astrocyte response to plaque pathology and acute neurodegeneration. AD female APOE4 carriers showed impaired induction of MGnD signature genes and astrocyte activation, including LGALS3 and GFAP respectively, supporting a conserved disease mechanism in a sex‐dependent manner.ConclusionAPOE4 impairs MGnD‐microglia in AD and prevents their crosstalk with astrocytes. Lgals3 is identified as important positive regulator for microglia–astrocyte crosstalk in response to AD pathology and provides a potential therapeutic target for treatment of AD.
The Effect of Depression in Instrumental Activities of Daily Living in Mild Cognitive Impairment: The mediating role of cognitive dysfuction
Authors: Jung Na‐Yeon , Ha YoungJi , Eom SungHui 
Published: December 2023

AbstractBackgroundGeriatric depression can affect on decline of various cognitive functions including executive function and can lead to disabilities in instrumental activities of daily living (IADL). Decline in IADL was related to conversion to dementia even though there was no decline in screening tests such as MMSE. Therefore it is important to manage the factors affecting IADL. We examined the relationship between depression, cognitive dysfunction and IADL in mild cognitive impairment (MCI) to reveal the effect of depression on IADL.MethodWe recruited 132 patients with MCI who visited the Department of Neurology at Pusan National University Yangsan Hospital from March 2019 to June 2022. Using the Short‐Geriatric Depression Scale (S‐GDS: cuf‐off 8), these patients were divided into 64 depressed groups (mean age 75±6.7) and 68 non‐depressed groups (mean age: 71±8.1). To evaluate cognitive function, the Seoul Neuropsychological Screening Battery, which consists of five domains: attention, language functions, visuospatial functions, memory, and executive functions, was conducted. K‐IADL (Korean Instrumental Activities of Daily Living) was conducted to evaluate IADL. We investigated the mediation effect of cognitive functions between depression and IADL using mediation analysis.ResultDepression and K‐IADL showed positive correlation (B = 0.023, p < 0.001). Mediation analysis of cognitive function between depression and IADL showed significant effect of executive function (B = ‐0.001, p = 0.019) and visuospatial function (B = ‐0.001, p = 0.045). Memory, language and attention domains had no significant mediation effect between depression and ADL.ConclusionIn our study, depression related to decline in IADL, and not only the effects of depression but also mediation effects of executive and visuospatial dysfunction could affect IADL. In terms of IADL maintenance, it is necessary to actively manage the depressed mood of MCI patients.
Influence of Insulin Resistance and Metabolic Dysregulation on Synaptic Protein Profile in SH‐SY5Y Neuroblastoma Cells
Authors: Yang Alexander J.T. , Mohammad Ahmad , Finch Michael , Tsiani Evangelina , Spencer Gaynor , Necakov Aleksandar , MacPherson Rebecca EK 
Published: December 2023

AbstractBackgroundBrain insulin resistance and metabolic dysregulation are significantly associated with Alzheimer’s disease development[1,2]. Metformin is the most prescribed type‐2‐diabetic drug and has been used to treat peripheral insulin resistance (IR) driven metabolic dysfunction through the activation of AMP‐kinase (AMPK)[3,4], but whether metformin is effective in improving brain metabolism is unknown. We have previously shown that chronic AMPK activation negatively impacts neuronal morphology and impairs synaptic protein content in healthy neurons[5]. However, whether AMPK activation under an IR state will exacerbate neuronal impairments is not known. Thus, we examined the effect of metformin‐driven AMPK activation on SH‐SY5Y cells with and without high‐insulin induced IR.MethodsRetinoic acid‐differentiated SH‐SY5Y neuroblastoma cells were treated for 48h with either 1) vehicle (Ctl), 2) 100 M insulin (INS, mimicking hyperinsulinemia), 3) 2 mM metformin (MET), or 4) a combination of INS/MET.ResultsINS‐treated cells demonstrated higher Akt S473, mTOR S2448, and p70s6k T389 phosphorylation, indicative of hyperactive mTORC1 signaling associated with brain IR. INS cells had lower insulin receptor‐ (IR‐) content and higher IRS‐1 S636 phosphorylation, further demonstrating insulin signaling abnormalities. MET increased AMPK T172 phosphorylation, and increased phosphorylation of its downstream effectors ULK S555 and raptor S792, which, collectively, is indicative of mTORC1 inhibition. These phosphorylation increases occurred alongside higher IRS‐1 and insulin receptor‐ content and reduced IR‐ content. INS/MET‐treated cells produced no change in AMPK T172 or raptor S792 phosphorylation but produced increased ULK S555 phosphorylation. INS/MET did not recover increased Akt S473, mTOR S2448, p70s6k T389, or IRS‐1 S636 phosphorlyation nor did it recover IR‐ content. No differences were seen between groups for pre‐/post‐synaptic protein content. INS and MET treatments showed reduced NeuN and synaptophysin content. INS/MET treatment showed reductions in synaptophysin. Morphologically, cell size & area, and neurite length & area all increased with INS and MET treatments, however, these increases were absent with the INS/MET treatment.ConclusionThese findings indicate that IR and MET impact neuronal morphology and reduce the development of mature neurons. These impairments are likely driven through Akt and AMPK signaling seperately and suggest that MET is not effective in treating IR‐driven impairments in the brian.
Brain Volumetry‐based Amyloid PET Positivity Prediction in Subjective Cognitive Decline Patients
Authors: Jung Wooseok , Yang Dong Won , Lee Chunghwee , Hong Yun Jeong , Ho SeongHee , Jeong Jee Hyang , Park Kee Hyung , Kim SangYun , Wang Min Jeong , Choi Seong Hye , Lee Dongsoo , Kang Junghyun , Kim Jinyoung , Lee Yeha ,   Alzheimer’s Disease Neuroimaging Initiative
Published: December 2023

AbstractBackgroundAmyloid beta PET screening for subjective cognitive decline (SCD) patients would identify a risk factor of Alzheimer’s disease (AD) at an early stage but is generally infeasible due to the high cost and radiation exposure. Brain volumetry using 3D T1 MRI integrated with genetic information can alternatively suggest amyloid positivity in SCD subjects.MethodIndividuals of age between 60 and 85 feeling cognitive decline and scoring 7% to 50% on the memory test while exceeding 7% of the other tests comprises the SCD dataset via Seoul Neuropsychological Battery (SNSB) scheme (n = 119; 26 Aβ+; 24 APOE4+). We measured the volume, volume to intracranial volume ratio, cortical thickness and their normative percentiles of 104 brain subregions, respectively, using VUNO‐Med DeepBrain, an automated brain volumetry and neurodegenerative disease diagnosis‐supporting software. The significance level is set to a = 0.005 to find differentiating regions between amyloid positive and negative groups. Furthermore, four machine learning models (Logistic Regression, Random Forest, XGBoost, TabNet) were trained using the combination of APOE4 information, age, and each of the six different volumetry results to predict amyloid positivity in SCD dataset. The training dataset (n = 102; 36 Aβ+; 31 APOE4+) consists of subjects from significant memory concern (SMC) cohort of ADNI2 and ADNIGO studies.ResultSwell of the choroid plexus and shrink of the lingual cortex (both p < .005) are statistically significant in Aβ+ SCD patients compared to the Ab‐ patients. The random forest model trained by the volume data plus APOE4 and age information showed the highest performance (accuracy = 0.79, AUROC = 0.75, precision = 0.81, recall = 0.79, F1 = 0.80) in the amyloid positivity prediction task among the 24 models, higher than the model without APOE4 information (accuracy = 0.70, AUROC = 0.71, precision = 0.77, recall = 0.70, F1 = 0.72).ConclusionThe result indicates a statistically significant difference in choroid plexus volume and lingual cortex thickness between Aβ+ and Aβ‐ SCD patients. In addition, using both APOE e4 information and brain volumetry is crucial for amyloid positivity prediction. This study was supported by a grant from the Ministry of Health and Welfare, HI18C0530.
DETECT‐AD (Digital Evaluations and Technologies Enabling Clinical Translation for Alzheimer’s Disease): A simulated anti‐amyloid clinical trial using digital biomarkers as primary outcome measures
Authors: Kaye Jeffrey A , Marcoe Jennifer , Mar Amanda B , Hanna Elise J , Pierce Aimee , Silbert Lisa C , Shang Yanan , Schwartz Daniel , Gothard Sarah , Mattek Nora , Au‐Yeung Wan‐Tai M. , Steele Joel S. , Beattie Zachary T 
Published: December 2023

AbstractBackgroundEarly detection and precise monitoring of cognitive and functional decline in persons with Alzheimer’s Disease (AD) in clinical trials is a high priority. Unfortunately, early detection and monitoring of the subtle and slow changes of disease with conventional cognitive testing and self‐report questionnaires has been fraught with poor sensitivity and lack ecological validity. Digital biomarkers using ambient sensing technologies may afford a more effective approach to conducting trials. Remaining to be established is the ability of this approach to fundamentally improve early AD treatment response readout in a formal clinical trial setting. A simulated clinical trial (DETECT‐AD: ClinicalTrials.gov, NCT05385913) is being conducted to determine how well continuously assessed, home‐based digital biomarkers may detect clinically meaningful changes in individuals with changing amyloid (Aβ) burdens in pre‐symptomatic AD.MethodClinically prodromal AD patients with estimable rates of AD progression based on Aβ Florbetapir‐PET status are enrolled divided n = 50:n = 50 into Aβ “positive” (higher amyloid burden) patients who predictably progress (as if they were receiving placebo) and Aβ “negative” patients progressing more slowly (representing the treatment group). A study‐provided multivitamin mimics RCT conditions and study drug adherence behavior. Baseline standard clinical and biomarker measures are obtained along with digital biomarkers (DB) captured with passive and active sensors (actigraphy, bed mats, IR sensing, e‐pillbox, computing/phone device use, weekly online reporting/cognitive assessment). Primary outcome is the change in a composite DB composed of measures in 4 domains: mobility, cognition, sleep, and socialization. Secondary measures are the relationship of DB to fluid biomarkers (plasma ptau181/217, amyloid, NfL) and MRI/PET measures.ResultTo date (01/16/2023), 46/100 have been enrolled with mean(SD): follow‐up = 27.0(7.9) weeks (no dropout); age = 78(6.6); 63% women; MoCA = 25.5(2.3); PET SUVR = 1.09(0.20), range: 0.850‐2.07. Exemplary baseline digital biomarker metrics are presented in the Table. Preliminary data shows an inverse Aβ‐SUVR correlation with mean steps/day (r = ‐.41, p = .012) and a positive correlation of MoCA with computer use (r = .61; p = .036).ConclusionHome‐based continuous capture of multi‐domain DBs is feasible in a clinical trial setting and may yield early meaningful indicators of clinically relevant changes in older adults with pre‐AD dementia. Further evidence will evolve as sample sizes and longitudinal follow‐up increases.
Circulating cell‐free mitochondrial DNA (ccf‐mtDNA) and memory in mild cognitive impairment (MCI) and Alzheimer’s disease (AD)
Authors: Song Bing Xin , Beroncal Erika , Andreazza Ana C. , Gallagher Damien , Marzolini Susan , Rapoport Mark J. , Charles Jocelyn , Herrmann Nathan , Oh Paul I. , Kiss Alex , Swardfager Walter , MacIntosh Bradley J. , Rajji Tarek K. , Siddiqui Mehreen , Vieira Danielle , Rivet Luc , Lanctôt Krista L. 
Published: December 2023

AbstractBackgroundCirculating cell‐free mitochondrial DNA (ccf‐mtDNA), a measure of mitochondrial dysfunction, is emerging as a potential biomarker for early Alzheimer’s disease (AD). Decreased levels of cerebrospinal fluid ccf‐mtDNA concentrations have been detected in early AD patients. Few studies have investigated peripheral ccf‐mtDNA in early AD or with cognitive measures, much less evaluating the role of physical activity within the relationships. Considering the hallmark of episodic memory impairment in early AD, we examined the association between serum ccf‐mtDNA and memory, while considering potential contributing factors, physical activity level and age.MethodsParticipants were diagnosed with mild cognitive impairment (MCI) or mild AD using the Diagnostic and Statistical Manual of Mental Disorders criteria for mild or major neurocognitive disorder. Serum ccf‐mtDNA concentration (copies/uL) was measured using quantitative polymerase chain reaction from circulating cell free DNA purified by spin columns with primer for the MT‐ND4 gene. Memory was assessed using the Word Recall Task from the Alzheimer’s Disease Assessment Scale‐Cog (ADAS‐Cog). Physical activity level was assessed by Leisure‐Time Exercise Questionnaire (LTEQ). Linear regression analyses were used to assess the association between ccf‐mtDNA levels and recall memory with a priori covariates, age and LTEQ score. Ccf‐mtDNA levels were log‐transformed prior to analyses due to significant departure from normality in Shapiro‐Wilk tests.ResultsOf 29 participants [17 (59%) male, 21 (72%) MCI], the mean (SD) age was 74.2 (8.7), years of education was 16.2 (2.2), Montreal Cognitive Assessment (MoCA) total score was 22.1 (3.3), LTEQ score was 36.2 (17.4), and ccf‐mtDNA levels were 2545.8 (2223.6) copies/uL. Higher ccf‐mtDNA was associated with worse recall [F(3,25) = 5.21, R2 = .39, p = .006]. Controlling for LTEQ and age, one log ccf‐mtDNA unit was associated with 1.87 (SE = .71) fewer words recalled (p = .01, f2 = .21).ConclusionIn this sample, higher serum ccf‐mtDNA concentrations were associated with worse recall, controlling for age and physical activity level. This relationship supports the potential involvement of mitochondrial dysfunction in cognitive functions and neurodegenerative diseases and suggest the need for further research to explore the role of physical activity and age with mitochondrial dysfunction and memory.
Treatment‐Induced Epigenetic Modifications in MCI and Probable Alzheimer’s Disease
Authors: Reading Christopher Lewis , Gordevicius Juozas , Haroon Jonathan , Jordan Kaya , Rindner Elisabeth , Ahlem Clarence N , Mahdavi Kennedy D , Surya Rama , Venkatraman Victoria , Yuan Harvey , Becerra Sergio A , Pourat Bijan , Kuhn Taylor P , Palumbo Joseph , Brooke Robert , Jordan Sheldon E 
Published: December 2023

AbstractBackgroundNE3107 is an oral small molecule, blood‐brain permeable anti‐inflammatory insulin sensitizer that binds ERK, inhibits inflammatory NFkB and TNF signaling in macrophage lineage cells, and in clinical studies for AD (NCT04669028) and Parkinson’s disease (NCT05083260). NE3107 does not inhibit homeostatic activity of ERK or NFkB, and has a good safety profile in preclinical, non‐clinical and clinical studies. Safety, clinical, biomarker and neuroimaging results from a 3‐month open‐label phase 2 study of NE3107 treatment of mild dementia (NCT05007820) were reported at CTAD 2022. We report here results of epigenetic clock studies from NCT05007820.MethodSubjects with CDR 0.5‐1 were consented, and blood was drawn, frozen and shipped for Horvath Clock DNA methylation (DNAm) epigenetic analysis (Horvath 2018 Aging 10:1758) at baseline and 3 months.ResultThe subject’s DNAmSkinBloodAge clock closely matched their chronologic age at baseline (+0.7 years). After 3 months of NE3107 (20 mg BID), the DNAmSkinBloodAge decreased (‐3.3 years, Table). Leptin is lower in AD, and DNAmLeptin is positively correlated with metabolic parameters waist/hip ratio, BMI, CRP, insulin, glucose and triglycerides (Lu 2022 Aging 14:9884). Dinucleotide (CpG) methylation in association with the leptin promotor (DNAmLeptin) decreased in all subjects (‐40%). DNAmPackYears is reported to be negatively correlated with time to mortality in both smokers and nonsmokers, and positively correlated with waist/hip ratio, CRP and triglycerides. DNAmPackYears also decreased (‐39%). Baseline DNAmMonocyte correlated with monocyte frequency but decreased (‐29%) after 3 months treatment without change in monocyte frequency. There were no significant changes in DNAmTcell, DNAmNK or DNAmGran.ConclusionNE3107 treatment significantly decreased biological age compared to chronological age and altered epigenetic measures correlating with metabolic parameters known to be associated with cognitive decline. DNAm decreases in monocyte/macrophage are associated with proinflammatory pathways in many disease states but aging epigenetic clocks may select for CpG methylation associated with inhibition of anti‐inflammatory pathways. NE3107 decreases in DNAmMonocyte, DNAmSkinBloodAge, DNAmLeptin and DNAmPackYears in MCI and AD subjects were associated with cognitive, biomarker and neuroimaging improvements. The data suggests that NE3107 may decrease methylation in promoters of monocyte/macrophage pathway regulators that can decrease inflammation and restore metabolic homeostasis in subjects with dementia.
Mapping the spatial transcriptomic signature of the hippocampus during memory consolidation
Authors: Chatterjee Snehajyoti 
Published: December 2023

AbstractBackgroundMemory consolidation relies on discrete spatial patterns of transcriptional events in the hippocampus. Despite the emergence of single‐cell transcriptomic profiling techniques, defining learning‐responsive gene expression across sub‐regions of the hippocampus has remained challenging.MethodWe utilized unbiased spatial sequencing to elucidate transcriptome‐wide changes in gene expression in the hippocampus following a learning experience, enabling us to define molecular signatures unique to each hippocampal subregion.ResultWe find that the CA1 pyramidal layer, CA1 stratum radiatum, CA1 stratum oriens, CA2/3 pyramidal layer, and dentate gyrus (DG) granular and molecular layers of the dorsal hippocampus exhibit distinct yet overlapping transcriptomic signatures. While the CA1 region exhibited increased expression of genes related to transcription regulation, the dentate gyrus (DG) showed upregulation of genes associated with protein folding. We demonstrate the functional relevance of subregion‐specific gene expression by genetic manipulation of the Nr4a transcription factor subfamily members selectively in the CA1 hippocampal subregion, leading to long‐term memory deficits. We have also shown that the hippocampus from postmortem Alzheimer’s disease and related dementia (ADRD) and a mutant tau mouse model of ADRD exhibit downregulation of Nr4a family members. We demonstrate the functional relevance of subregion‐specific gene expression by genetic manipulation of a transcription factor selectively in the CA1 hippocampal subregion, leading to long‐term memory deficits and connecting these findings with ADRD.ConclusionOur work demonstrates the power of spatial molecular approaches to reveal that the subregions of the dorsal hippocampus respond to learning by exhibiting distinct transcriptomic signatures. Our attempt to elucidate the spatial transcriptomic signature of memory provides the groundwork for future studies to understand the precise gene expression patterns underlying memory consolidation, and whether these signatures are affected in neurodegenerative diseases associated with memory impairments.
Graph theoretical analysis demonstrates associations among cortical network segregation, β‐amyloid status, and reward‐based learning in older age
Authors: Chen Hsiang‐Yu , Hsu Ming , Jagust William J. , Berry Anne S. 
Published: December 2023

AbstractBackgroundAs humans age, brain networks supporting cognition show alterations in functional connectivity patterns consistent with network dedifferentiation. Here we examined the extent to which Alzheimer’s disease (AD)‐related β‐amyloid (Aβ) pathology exacerbates functional dedifferentiation in aging and is associated with reduced probabilistic reward‐based learning.Method27 young and 47 cognitively normal older adults underwent 3T functional magnetic resonance imaging (MRI) while performing a novel probabilistic learning task. The task required participants to learn the identity of real‐estate agents as “winning,” “losing,” or “break‐even” based on their success in selling houses for a profit. We used graph theoretical analysis and applied 400 regions of interest to identify age‐related changes in functional brain networks during early and late learning phases in the task. Older adults were characterized as Aβ‐ (n = 34) or Aβ+ (n = 13) using [11C]Pittsburgh Compound‐B positron emission tomography. Analyses focused on the two graph theory measures commonly linked to dedifferentiation (i.e. loss of segregation): clustering coefficient and modularity.ResultsYoung adults showed better learning performance, followed by Aβ‐ older adults and then Aβ+ older adults, but there was no significant age difference between young and Aβ‐ older adults (Fig. 1). Young adults also showed a higher clustering coefficient, which indicates greater network segregation, followed by Aβ‐ older adults and then Aβ+ older adults (Fig. 2A and 2B). Considering the learning phase, we found differences between the young and both Aβ‐ and Aβ+ older adults in the early learning phase (Fig. 2A), and differences between young and only Aβ+ older adults in the late learning phase (Fig. 2B). Analyses of modularity showed similar patterns of results, though the main effect of group was not significant (Fig. 2C and 2D). There was an interaction between network segregation and group to predict learning performance. Only Aβ‐ older adults with higher network segregation exhibited better learning performance (Fig. 3).ConclusionThese findings indicate Aβ is associated with functional network dedifferentiation and poorer learning performance. For Aβ‐ older adults, successful maintenance of brain network segregation may underlie the preservation of “youth‐like” cognitive performance.