bluuebunny/crossref_metadata_2025_split huggingface dataset:
Higher amyloid burden is associated with faster reduction in cerebral blood flow: a longitudinal study
Authors: Zhao Tianrui , Tang Jianing , Terner Jamie , Joe Elizabeth B , Braskie Meredith N , Chui Helena C , Marmarelis Vasilis , Yan Lirong 
Published: January 2025

AbstractBackgroundAmyloid accumulation is one of the main pathophysiological hallmarks of Alzheimer’s disease (AD) and is closely associated with neuronal dysfunction and cognitive decline. Except for amyloid pathology, accumulating evidence has shown vascular dysfunctions, such as reduced cerebral blood flow (CBF), also contribute to AD pathophysiology. However, there remains limited research about the longitudinal changes between amyloid accumulation and CBF. The present study aims to address the gap through conducting both cross‐sectional and longitudinal studies to investigate the relationship between amyloid burden and CBF changes.Method168 participants (72.5 ± 8.5 years, 86 female) were enrolled in this study. CBF measurements were obtained from each participant using single‐delay pCASL. Among participants, 94 underwent amyloid PET scans. 72 out of them received a second pCASL MRI scan for one‐year follow‐up. Standardized update value ratio (SUVR) was calculated from PET data. A global SUVR of 1.08 was used to define amyloid positivity. Mean CBF and SUVR were extracted from gray matter and nine AD‐related brain regions.Linear mixed effects model was employed to examine the association between baseline CBF and baseline SUVR with correcting for age and gender; A paired t‐test assessed CBF difference between the amyloid positive and negative groups; Multivariate linear regression was performed to investigate the association of baseline SUVR level with CBF changes by considering the follow‐up CBF as dependent variable and baseline CBF, SUVR level, time‐gap, age, and gender as independent variables.ResultBaseline CBF showed significant correlations with age in gray matter and 8 AD‐related regions (Figure 1). Baseline CBF demonstrated a strong association with amyloid positivity in gray matter and 5 AD‐related regions (Figure 2). No significances were observed between baseline CBF values and SUVR levels in all 9 regions. However, baseline SUVR level was significantly associated with longitudinal CBF changes in 8 AD related regions (Figure 3). These results suggest a higher amyloid burden may predict faster CBF reduction during the progression of AD.ConclusionOur results demonstrate that longitudinal CBF changes are strongly associated with baseline SUVR levels both globally and regionally, suggesting that increased amyloid burden may affect neurological dysfunction leading to CBF reduction over time.
Shared and distinct molecular signatures of astrocyte subtypes across brain regions and neurodegenerative diseases
Authors: Saliu Ibrahim Olabayode , Zhao Guoyan 
Published: January 2025

AbstractBackgroundAstrocytes are specialized glial cells that play crucial roles in the brain by providing metabolic and trophic support for the neurons. They become reactive (activated) and heterogeneously respond to neuropathology such as injuries and neurodegenerative diseases (NDs). High‐throughput single‐nucleus (snRNA‐seq) RNA sequencing has enabled a profound understanding of cell type heterogeneity. However, the number of astrocyte subpopulations in different regions of the brain, and the similarities and differences among these subpopulations in healthy and disease conditions are not clear.MethodWe performed uniform data analysis using the same algorithm and parameters on astrocytes from postmortem human brain single‐nucleus RNA‐sequencing (snRNA‐seq) data obtained from eight datasets with seven different brain regions of normal control subjects and subjects with different NDs including Alzheimer’s disease (AD), dementia with Lewy body disease (DLBD), Parkinson’s disease (PD), Parkinson’s disease with dementia (PDD), Huntingtin disease (HD), or Nasu‐Hakola disease (NHD). We identified astrocyte subpopulations and systematically compared astrocyte subpopulations and defined their common marker gene set across seven brain regions in six disease conditions. We conducted functional enrichment pathway analysis on the marker genes to understand the putative contribution of these subpopulations to NDs including across different brain regions.ResultWe identified 3‐6 distinct astrocyte subpopulations by examining the expression of conserved marker genes across all the different datasets. Two subpopulations were shared across all the NDs and brain regions, representing homeostatic (Ast‐0) and activated transcriptional states (Ast‐1 and Ast‐2), while the other subpopulations are unique to different datasets. Functional enrichment analysis revealed distinct and shared pathways among astrocyte subpopulations across all brain regions.ConclusionWe identified astrocyte subpopulations shared across all the brain regions and disease conditions with shared molecular marker genes but also regional‐ or disease‐specific gene expression features. We also observed disease‐ or brain region‐specific astrocyte subpopulations. These results suggest that regional differences in astrocyte subpopulations or gene expression could underly regional differences in brain susceptibility to different neurodegenerative diseases.
Efficacy of an inhibitor of GSK‐3β in an Alzheimer’s Disease Mouse Model
Authors: Ghuman Mobeena , Boutajangout Allal , Atta Abdurrahman , Kaddioui Rim El , Kozikowski Alan P , Wisniewski Thomas 
Published: January 2025

AbstractBackgroundNeurofibrillary tangles (NFTs), one of the hallmarks of Alzheimer’s disease (AD), are composed of highly phosphorylated forms of the microtubule‐associated protein tau. Phosphorylation results from the activity of several threonine/serine kinases, and increased expression of glycogen synthase kinase‐3β (GSK‐3β). These are involved in the formation of paired helical filament (PHF)‐tau, which induces the formation of NFTs. Preclinical and clinical studies have supported that GSK‐3β inhibition may have therapeutic benefits for AD. We assessed the therapeutic effect of our novel GSK‐3β inhibitor, ING‐135, in an animal model of AD.MethodhTau/PS1 mouse models were injected intraperitoneally with ING‐135 (30 mg/Kg; n = 15 per group) starting at 3 months of age, three times a week for three months, and control mice received saline only. Animals went through different behavioral tasks and brain tissue was subsequently harvested for analysis of treatment efficacy.ResultTreated animals (n = 15) did not show significant differences when compared to controls on sensorimotor tasks (i.e., Traverse beam, Rotarod, and Locomotor activity). Significant behavioral improvement was noted in treated mice on three tasks using a closed field symmetrical maze (Day 1 one‐tailed t‐test p = 0.0036; Day 2 one‐tailed t‐test p = 0.0118; Day 3 one‐tailed t‐test p = 0.0002). Immunohistochemistry analysis was performed on brain sections of treated animals and controls, using monoclonal antibodies PHF1 and CP13. Histology analysis showed a reduction of tau pathology in the motor cortex and hippocampus of treated animals (one‐tailed t‐test p = 0.0001, p = 0.0002; respectively). No significant differences were observed between the two groups with GFAP, and Iba‐1 showed a reduction of microglia in the cortical area (p = 0.05). Results were not significantly different in the dentate gyrus. Further biochemical analyses are underway.ConclusionOur novel inhibitor of GSK‐3β (ING‐135), improves cognitive decline (long‐term memory) and decreases tau phosphorylation in treated animals versus controls, in the absence of toxicity.
The role of manganese over‐exposure in glutamate dysregulation and EEG outcomes in a mouse model of Alzheimer’s disease
Authors: Buchanan Rebecca A. , Harrison Fiona E. 
Published: January 2025

AbstractBackgroundManganese (Mn) is an essential metal that serves as a cofactor for metalloenzymes important in moderating the glutamate/glutamine cycle and other oxidative stress pathways. Typically, Mn is acquired through the diet, however, Mn overexposure can arise through drinking inadequately treated well water or inhalation of Mn‐containing industrial byproducts. Mn toxicity disrupts dopaminergic neurotransmission resulting in a Parkinsonian disorder referred to as manganism. More recently, increased focus has been given to the role Mn toxicity in the progression of other neurodegenerative diseases including Alzheimer’s Disease (AD). Excess Mn may contribute to dysregulation of astrocytic glutamatergic transport, leading to elevated extracellular glutamate, excitotoxicity, and ultimately cell death, which are all key features of early AD pathology. We hypothesized that Mn toxicity drives glutamatergic signaling dysfunction to exacerbate pathology seen in AD including excitotoxicity and epileptiform activity.MethodAPPswe/PSEN1dE9 mice, a mouse model of AD, and wild‐type littermates of both sexes were exposed to 50mg/kg MnCl2·4H2O or the vehicle subcutaneously three times over the course of a week as an acute high dose exposure of Mn. Increased seizure susceptibility in response to manganese and kainic acid (kainate receptor agonist) exposure was analyzed through surface cortical electroencephalogram recordings. Changes in glutamate reuptake transporter protein and mRNA expression from cortical and hippocampal tissue were quantified using western blot and qPCR.ResultAPPswe/PSEN1dE9 mice have more cortical spiking activity over the course of exposure compared to WT mice. Effects of kainic acid were quantified over four hours and we found that Mn‐exposed mice have significantly decreased spiking over the first hour compared to vehicle treated mice. However, spiking activity increased over time in Mn‐treated mice, while spiking activity decreased in vehicle treated mice resulting in a significant reaction between treatment and time. There was no difference in spiking at the end of the four‐hour observation period.ConclusionDynamic responses to kainic acid and changes in glutamate reuptake transporter expression are consistent with glutamatergic changes that can contribute to excitotoxicity. Taken together, these findings support the hypothesis that manganese acutely interferes with glutamate functioning and could exacerbate phenotypes observed in AD.
Subjective and objective memory among older adults: Examining the intersecting role of depression and locus of control in the ACTIVE study
Authors: Weigand Alexandra J. , Clark Alexandra L. , Garcia Mary Ellen , Parisi Jeanine M , Zahodne Laura B. , McDonough Ian M , Marsiske Michael , Thomas Kelsey R. 
Published: January 2025

AbstractBackgroundSubjective memory concerns (SMC) may be a sensitive marker of future cognitive declines. However, there are multiple factors that can impact the predictive utility of SMC. Prior studies have demonstrated the effect of depression on SMC. Further, perceived control over one’s situation as measured by locus of control (LOC) has been linked to both depression and SMC. Therefore, the current study examined the moderating effect of depressive symptoms on the association between SMC and memory decline and further investigated whether this interaction varied as a function of internal LOC.MethodThis study included 2721 older adults without dementia from the Advanced Cognitive Training for Independent and Vital Elderly (ACTIVE) study. Predictors of interest included SMC, depressive symptom severity, and internal LOC. Multilevel mixed models examined the 4‐way interaction between internal LOC, depressive symptoms, SMC, and time on 10‐year rate of change on an objective memory factor score.ResultThere were significant independent effects of SMC (t = ‐2.40, p = .02) and depressive symptoms (t = ‐3.48, p < .001) on 10‐year memory trajectories, but no significant interaction between SMC and depressive symptoms (t = 1.45, p = .15). However, there was a significant interaction between internal LOC, depressive symptoms, and SMC on memory trajectories (t = ‐3.52, p < .001). Specifically, in the context of lower internal LOC, depressive symptoms strengthened the association between SMC and objective memory trajectories, whereas depression was not a significant moderator among individuals with higher LOC.ConclusionFindings demonstrate the complexities of SMC in predicting memory decline and highlight intersecting individual‐level factors that may influence the predictive utility of SMC among older adults. Specifically, we found that in individuals with lower internal LOC (e.g., less belief they can control their own cognitive aging), the strength of association between SMC and memory decline was strengthened by depressive symptoms. Future research will examine additional interacting factors (e.g., demographics, sociocontextual variables) to help provide a nuanced understanding of when SMC are most prognostically useful.
Targeting and reducing neuronal ceramide overaccumulation in 5xFAD mice improves AD pathologies and cognitive function
Authors: Wilkerson Joseph L , Chaix Amandine , Summers Scott A , Holland William L 
Published: January 2025

AbstractBackgroundNeurodegenerative disorders such as Alzheimer’s Disease (AD) are increasingly associated with irregular lipid accumulation. Dysfunction in the catabolism of sphingolipids leads to many neurodegenerative disorders but has only recently garnered interest in AD. Excess ceramide deposition has been observed in Aβ‐plaques, plasma, and cerebrospinal fluid in AD patients and AD mouse models. Ceramide‐lowering strategies have been underexplored as a treatment for AD and may prove to be a beneficial target in mitigating the disease.MethodWe have used both pharmaceutical and genetic approaches to target ceramide accumulation in the 5xFAD mouse model of AD. Myriocin was used block ceramide de novo synthesis. The drug was administered in mice on a normal chow diet and an obesogenic pro‐ceramide high‐fat diet. As a genetic approach, we developed an inducible loss‐of‐ceramides model by overexpressing Asah1, the gene encoding the ceramide degrading enzyme acid ceramidase specifically in neurons. We assessed the loss of ceramides as a preventative treatment (overexpression beginning at 6‐weeks) or mature disease treatment (overexpression beginning at 30 weeks). We assessed Aβ plaques and the activation and quantity of glia by immunohistochemistry. Cognitive behavior was assessed using the Barnes maze and fear conditioning chambers. Frailty index scores were generated through clinically equivalent tests.ResultMyriocin treatment reduced ceramide accumulation in the hippocampus of 5xFAD mice. Vehicle‐treated 5xFAD mice had significant memory deficits compared to myriocin‐treated mice. The myriocin‐treated mice had smaller and fewer Aβ plaques, fewer hippocampal microglia, and a reduction in astrocyte arborization and numbers in hippocampus and cortex. Early overexpression of Asah1 in neurons improved memory loss in fear conditioning chambers. Plaque size and number remained unchanged. However, IBA1+ microglia/monocyte and GFAP+ astrocyte activation and migration were eliminated in neuronal Asah1 overexpressing mice. Plaques in these mice had no associated glia and glia morphology resembled wild‐type mice. Late overexpression of Asah1 in neurons led to improved frailty index scores compared to 5xFAD mice at one year of age.ConclusionPharmaceutical inhibition of ceramide synthesis improved cognitive outcomes and reduced AD pathologies in 5xFAD mice. Reducing ceramides specifically in neurons in 5xFAD mice eliminated gliosis and improved cognitive function.
Isolation of single neuronal nuclei by phospho‐tau accumulation in Alzheimer’s disease brain
Authors: Jin Bowen , Naik Samuel , Kirkham Samantha L , Qian Xuyu , Zhou Zinan , Oakley Derek , Frosch Matt P. , Hyman Bradley T. T , Huang August Yue , Miller Michael B 
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by the deposition of amyloid‐beta and hyperphosphorylated tau (P‐tau) proteins in the brain. P‐tau accumulates in neurons and is strongly associated with AD severity and affected brain regions. However, only a subset of neurons in AD exhibit tau pathology. The molecular mechanisms behind heterogeneous tau pathology and how it contributes to AD are not well understood.MethodWe developed a fluorescence‐activated nuclear sorting (FANS) method to separate P‐tau+ neuronal nuclei from P‐tau‐ neuronal nuclei from the same brain tissue. To validate the specificity of P‐tau+ neurons, we mixed non‐AD control tissue with AD tissue and examined the origin of neuronal nuclei based on their genotype. We also subjected nuclei with P‐tau signal from FANS to immunofluorescence microscopy to examine the morphology and localization of P‐tau aggregates.ResultsWe observed disease‐specific P‐tau signal for nuclei in advanced AD (Braak stage V‐VI) cases. These P‐tau+ nuclei are highly distinguished from the P‐tau‐free nuclei. Confocal immunofluorescence microscopy showed P‐tau adherent to the outside of nuclei that exhibited P‐tau signal by FANS. We demonstrated that the nuclei sorting method based on P‐tau levels can highly enrich for P‐tau+ nuclei (>380 fold) and has a high accuracy of 98% based on the mixing experiments. In addition, we were able to obtain high‐quality single‐cell genome amplification for P‐tau‐sorted nuclei using primary template‐directed amplification (PTA), permitting single‐nucleus genome interrogation.ConclusionWe developed a highly efficient method using fluorescence‐activated nuclear sorting (FANS) to separate the population of P‐tau+ neuronal nuclei in AD brains. This method allows interrogation of human neuronal nuclei based on single‐cell tau pathology and enables single‐cell genomic studies of heterogeneous tau pathology in AD, toward insight into disease pathogenesis and therapeutic targets.
Sensitivity of Remote App‐Based Assessment of Cognition to Sleep‐Mediated Differences in Cognitive Functioning Among Older Adults
Authors: Rovere Rachel , Liebenberg Erin , Halberstadter Kimberly , Wolk David A , Mechanic‐Hamilton Dawn 
Published: January 2025

AbstractBackgroundThis study assesses the sensitivity of the mobile cognitive app performance platform (mCAPP), a mobile and engaging cognitive assessment tool, to participant sleep duration.MethodThe mCAPP includes three gamified tasks: a memory task (“Concentration”), a stroop‐like task (“Brick Drop”), and a digit‐symbol coding‐like task (“Space Imposters”). For all games, shorter reaction times and fewer guesses indicates better performance. The cohort included 50 participants (72% female; age = 71.9±4.5; education = 16.8±2.3; 51% white; 49% Black/African American) without cognitive impairment who are enrolled in the Penn ADRC cohort. Sleep data was collected via actigraphy (Fitbit). Game performance and overnight sleep prior to gameplay were analyzed as a whole and grouped by fewer (quartile 1; Q1) and higher (quartile 4; Q4) minutes of sleep.ResultThe average number of minutes of sleep was 378.0±96.5. Overall, minutes of sleep showed a significant negative correlation with reaction time on Space Imposters (ρ = 0.001). Participants with the fewest minutes of nighttime sleep performed slower than those with the most sleep on Space Imposters (Q1 M = 2.73; Q4 M = 2.40; p<.001), Brick Drop (Q1 M = 1.58; Q4 M = 1.31; p = .004), and Concentration (Q1 M = 5.25; Q4 M = 5.02; p = .006). There was not a significant difference in number of errors on Space Imposters (p = 0.53) or Brick Drop (p = 0.45) when comparing performance of participants with lower and higher quartiles of sleep, but there was a significant difference in the number of guesses on Concentration (Q1 M = 14.91; Q4 M = 12.80; p = 0.01).ConclusionThe mCAPP can remotely detect differences in cognitive performance related to nighttime sleep prior to gameplay. Future studies will examine differences in performance related to the time‐of‐day gameplay occurs (how long after overnight sleep) and whether performance is affected by daytime napping. A larger data set will also be used to fully determine the sensitivity of mCAPP to participant sleep duration and examine within‐participant effects.
Investigating the effects of increasing O‐GlcNacylation in Alzheimer’s disease in the TgF344‐AD rat model
Authors: Garcia Melissa L , McMahon Lori L , Jackson Nateka L 
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD) pathology can start accumulating 20‐30 years before cognitive symptoms occur, with increases in inflammation, amyloid‐β (Aβ), and hyperphosphorylated Tau during this time. Previous studies have shown that the post‐translational modification of a single N‐acetylglucosamine moiety to serine or threonine residues to cytosolic or nuclear proteins, known as O‐GlcNAcylation, can modify a plethora of cellular processes, including the processing of the amyloid precursor protein, competing with phosphorylation on tau, as well as having anti‐inflammatory effects. This study is designed to evaluate how increasing O‐GlcNAcylation is impacting AD pathology in the most comprehensive AD rat model to date, the TgF344‐AD rat model.MethodFor these experiments, we used 6‐month‐old TgF344‐AD (Tg) rats and non‐transgenic (nTg) littermates injected with 10mg/kg of thiamet‐G (TMG), an inhibitor of O‐GlcNAcase, (nTg‐TMG or Tg‐TMG) or saline (nTg‐S or Tg‐S) as a control, 3 times a week from 6‐9 months. We then sacrificed the animals via cardiac perfusion with oxygenated artificial cerebrospinal fluid before splitting the brain in half; one hemisphere to be drop fixed in PFA for immunohistochemistry and half to be sub dissected and flash frozen for protein analysis.ResultWe have preliminary results that confirm significant increases in GFAP, Iba1 and Amyloid‐β in Tg‐S rats compared to nTg‐S rats, however GFAP and Iba1 protein levels in Tg‐TMG rats are no longer significantly different from nTg‐S rats after 3 months of TMG injections to increase O‐GlcNAcylation. We have also evaluated noradrenergic innervation into the dentate gyrus using anti‐tyrosine hydroxylase (TH) immunohistochemistry and confocal imaging to evaluate if increasing O‐GlcNAc protects against loss of TH innervation of the dentate gyrus, and have so far confirmed our previous results at this time point; TMG treated animals are not significantly different from their saline controls.ConclusionWe report that increasing O‐GlcNAcylation from 6‐9 months in the TgF344‐AD rats is reducing reactive astrocytes. While this could be beneficial to preserving their function and neuronal health, this work is still ongoing. We are working to increase our sample size, and to examine the locus coeruleus for changes in hyperphosphorylated tau and other biomarkers.