bluuebunny/crossref_metadata_2025_split huggingface dataset:
Association of Chronic Anti‐GERD Medication Usage and Cognitive Decline in a Racially Diverse Elderly Population
Authors: Holland Thomas Monroe , Dhana Klodian , Agarwal Puja , Krueger Kristin R , Desai Pankaja , Liu Xiaoran , Beck Todd , Schneider Julie A , Rajan Kumar B 
Published: December 2023

AbstractBackgroundIt is understood that early medical intervention of various diseases, like cardiovascular or gastroenterological, is a potential way to mitigate the progression of cognitive decline and dementia. However, some medications’ mechanisms of action (MOA), may alter the metabolism of foods and absorption of nutrients and inhibit neurotransmitters. The long‐term influence of chronic medication use on cognition in a racially‐diverse elderly population is unknown. As such, we aim to investigate how chronic use of specific Anti‐GERD medications (e.g., proton pump inhibitors (PPI) and histamine 2 receptor antagonists (H2RA’s), may be associated with global cognitive decline and cognitive functional domainsMethodUtilizing data collected from a long‐running, community‐based study, the Chicago Health and Aging project (CHAP) which started in 1993, we examined the association of anti‐GERD medication use and cognition in n = 7742, 1268 (16%) PPI users and 939 (12%) H2RA users, aged ≥65 years. This study sample consists of 63% African American (AA) participants and 60% female participants. Recruitment and data collection occurred in triennial cycles. Medication use was assessed through direct observation while neuro‐cognition was evaluated using a battery of 4‐standardized cognitive tests. Using linear mixed effects change‐point models, adjusted for age, sex, education and race, we investigated whether chronic anti‐GERD medication usage is associated with cognitive declineResultOf anti‐GERD medication users, after starting the medication, chronic use of PPI’s was associated with a faster rate of global cognitive decline β = ‐0.028 (p≤0.000), memory score β = ‐0.023 (p≤0.000) and speed score β = ‐0.012 (p≤0.034). H2RA’s were not associated with global cognition or memory score but were suggestive for speed score β = ‐0.011 (p≤0.057). In models stratified by race and separately, sex, after starting, chronic PPI use was associated with faster global cognitive decline in AA β = ‐0.030 (p≤0.000), White β = ‐0.026 (p≤0.001) and female β = ‐0.037 (p≤0.000) but not male individuals. H2RA’s were only associated with faster global cognitive decline in White individuals β = ‐0.025 (p≤0.039)ConclusionChronic use of PPI’s and H2RA’s may be associated with faster rates of global cognitive decline and memory & speed scores in an elderly population. The associative results presented, demonstrate the need for further investigation into how medication usage potentially impacts cognition
Alzheimer’s disease‐associated post‐translational modifications of tau influence tau propagation
Authors: Dickson John R , Fernandes Analiese R , Sobolewski Robert , Fan Zhanyun , Hyman Bradley T. 
Published: December 2023

AbstractBackgroundIn Alzheimer’s disease (AD), tau accumulates with a stereotyped progressive involvement of brain regions. The cellular mechanism for this is the neuron‐to‐neuron propagation of tau, but the factors that influence tau propagation are not fully understood. We hypothesize that AD‐associated post‐translational modifications (PTMs) of tau reduce its propagation since lysines are critical for LRP1‐mediated tau uptake.MethodA construct was designed to model tau propagation in Chinese hamster ovary (CHO) cells and allow identification of donor and recipient cells by immunocytochemistry and flow cytometry. In addition to the wildtype (WT) tau sequence, constructs were made with pseudophosphorylation and pseudoacetylation mutations corresponding to the phosphorylations and acetylations found on low molecular weight (LMW) and high molecular weight (HMW) tau species in AD brains. Additionally, individual PTM mimic mutations corresponding to PTMs of the LMW tau species were made. The constructs were transfected into CHO cells and tau propagation was assessed by flow cytometry after 48 hours. Statistical analysis was performed by ANOVA with adjustment for multiple comparisons.ResultTau propagation using this cell culture model was demonstrated by immunocytochemistry and flow cytometry. Comparison of the WT, LMW‐mimic (8D2Q mutant), and HMW‐mimic (20D3Q mutant) tau propagation constructs revealed that the 8D2Q and 20D3Q mutants displayed reduced tau propagation compared to WT by 23.7% (p = 0.0186) and 26.5% (p = 0.0087), respectively. Comparing the ten single mutant constructs to WT, T181D and T231D showed increased tau propagation by 20.3% (p = 0.0002) and 15.9% (p = 0.0094), respectively. Compared to WT, T217D, K281Q, K353Q, and S404D showed reduced tau propagation by 17.3% (p = 0.0030), 15.3% (p = 0.0123), 23.7% (p <0.0001), and 16.6% (p = 0.0046), respectively.ConclusionThe mimics of AD‐associated tau PTMs found on LMW and HMW tau reduce tau propagation, consistent with the initial hypothesis. The impact of individual PTM mimics on tau propagation is variable, but notably both pseudoacetylation mimics reduce propagation, possibly due to lower affinity with LRP1. Understanding how AD‐associated tau PTMs impact tau propagation may suggest novel targets to slow the progression of AD pathology.
Alzheimer’s disease risk genes are differentially expressed upon Lipopolysaccharide stimulation in a myelogenic cell model
Authors: Arnesen Peter Mikael , Wettergreen Marianne , You Panpan , Fladby Tormod 
Published: December 2023

AbstractBackgroundLipopolysaccharides (LPS) is a molecule present in the outer membrane of Gram‐negative bacteria. Previous studies have shown that LPS treatment can lead to upregulated pro‐inflammatory and chemotactic cytokines, or elevate the expression of anti‐inflammatory factors in mouse or cell models. Inflammation is seen around amyloid plaques and around small cerebral vessels with Ab1‐40 deposits in AD brains. Increased levels of LPS have been found in the hippocampus of patients with Alzheimer’s disease, compared to age‐matched controls. Other studies demonstrated that LPS is also present and associated with white matter injury in AD and aging brains. Continued inflammation activates microglia and macrophages, which are ialso localized in perivascular tissue. However, to what extent the increased inflammation influences the expression of AD risk genes in myelogenic cells is not well known. Here we utilized RNA sequencing on THP‐1 derived macrophages using Aβ and LPS as stressors to further elucidate this.MethodWe performed RNA sequencing on THP1‐derived macrophages, with or without Aβ and LPS stimulation. 50 known AD risk genes were cross‐checked against the differentially expressed genes discovered. Furthermore, KEGG pathway analysis was performed on the Aβ versus the LPS and Aβ group.ResultOut of 50 AD risk genes, we identified a total of 24 genes in the various comparison groups (Figure 1). 14 AD risk genes were discovered in all the groups: TREM2, LILRB2, BIN1, TNIP1, CD2AP, CD33, CASS4, MS4A4A, NCK2, ADAMTS1, SPI1, RIN3, ECHDC3, AGRN (Figure 1 and2). KEGG pathway analysis pointed out TNF signaling pathway, lysosome, endocytosis and ubiquitin mediated proteolysis as enriched for cells stimulated by LPS with Aβ present (Figure 3).ConclusionOur study demonstrates that LPS activates inflammatory responses in myelogenic cells that further affects AD risk gene expression. Enriched pathways not only relate to Aβ uptake and clearance, but also reflect AD pathology. LPS and/or LPS induced inflammation may be a significant initiator or progressive contributor to inflammatory degeneration in AD.
Smoking History and Higher Pack Years Predict Brain Atrophy in 9646 Healthy Individuals
Authors: Meysami Somayeh , Raji Cyrus A. , Hashemi Sam , Garg Saurabh , Akbari Nasrin , Nguyen Thanh Duc , Gouda Ahmed , Chodakiewitz Yosef Gavriel , London Sean , Merrill David A. , Attariwala Raj 
Published: December 2023

AbstractBackgroundSmoking is a risk factor for both Alzheimer and vascular dementia. Understanding this risk requires an investigation of how smoking influences brain volume loss on MRI, a biomarker for neurodegeneration.MethodIn total, 9646 healthy participants from 4 sites were scanned on 1.5T MR with a whole‐body MR imaging protocol. Core whole body sequences included whole body coronal T1, STIR from vertex to feet, whole‐body axial DWI from vertex to proximal‐thighs and axial T2 TSE without fat suppression from skull base to pelvis. Brain sequences were T1 MPRAGE and 2D FLAIR. Deep learning volumetric software, FastSurfer, trained on over 134 participants age 27‐66, segmented 96 brain volumes. Smokers versus non‐smokers were compared by gray and white matter volumes normalized to total intracranial volume using a two tailed t‐test. Partial correlation analysis was done between pack years and brain volumes, controlling for age, sex, and total intracranial volume (TIV). The Benjamini Hochberg False Discovery Rate of 5% accounted for multiple comparisons.ResultOverall, the sample had an average age of 52.9±13.1 years with 3123 individuals (32.3%) self‐reporting a history of smoking with 3.72±10.08 pack years. The remaining 6523 persons (67.7%) were non‐smokers. Participants who smoked were older than non‐smokers (p = 0.024) and 51.55% were men versus 52.8% in the non‐smoker group (p = .218). Individuals with a history of smoking had lower normalized gray and white matter volumes compared to non‐smokers (t = 8.95, p = 4.39e‐19). Adjusting for age, sex, and TIV co‐variates and multiple comparisons, higher pack years of smoking predicted brain volume loss in: total gray matter volume (Partial R = ‐0.06, p = 2.19e‐8), total white matter volume (Partial R = ‐0.06, p = 4.26e‐9), hippocampus (Partial R = ‐0.05, p = 6.26e‐6), frontal cortex (Partial R = ‐0.06, p = 1.34e‐10), temporal lobes (Partial R = ‐0.06, p = 3.24e‐8), parietal lobe (Partial R = ‐0.04, p = 0.0008), orbital frontal cortex (Partial R = ‐0.05, p = 2.19e‐8), posterior cingulate gyrus (Partial R = ‐0.05, p = 2.97e‐7).ConclusionBoth smoking history and pack years are related to lower whole brain and regional volumes.
Social Assistive Robotics to Motivate Cognitive Training in Patients with Chronic Depression
Authors: Schüssler Sandra , Paletta Lucas , Reininghaus Eva , Macher Michael , Fellner Maria , Russegger Silvia , Lenger Melanie , Pszeida Martin , Orgel Thomas , Draxler Sandra , Häussl Alfred , Nina Dalkner , Spat Stephan , Pötz Gloria , Zuschnegg Julia 
Published: December 2023

AbstractBackgroundApproximately 280 million people in the world suffer from depression, which can become chronic and often leads to cognitive problems. International literature shows that depression is known as one of the 12 main modifiable risk factors for dementia, and therefore, cognitive training is essential to foster cognition and to reduce the risk for dementia. In the last years new technologies, like robots, have been developed to support health care professionals with limited resources in their daily practice. The aim of the Austrian project AMIGA is to develop and test a gender‐sensitive and customizable Social Assisting Robotic Technology (SAR) including a cognitive training to enhance cognition and to improve the quality of life of people with chronic depression in psychiatric hospitals.MethodIn the first step of the project, the requirements of the target group will be determined using qualitative and quantitative methods (e.g. survey, interviews). Based on the results, the interactive SAR prototype will be developed which will use human‐robot interactions to motivate users to perform cognitive training with the BRAINMEE‐App on a daily basis. Target group‐specific as well as gender‐sensitive content for holistic stimulation with visual, auditory and interactive elements will be included. The prototype will then be tested in a usability study with 12 end users including patients to revise the robot. At the end, a randomized controlled trial with additional interviews including 60 patients will be conducted to test the final robotic platform.ResultAt the conference, the first results of the project will be presented.ConclusionAMIGA is the first project to investigate, on a scientific basis using neuropsychological theories, care requirements and human factor measurement technologies, the fundamental design parameters for interactions with social robotics, which contribute to increasing motivation for cognitive training, to efficiently relieve stress and strengthen the resilience of patients with depression during training. AMIGA, as a research prototype, will lay the foundation for future system developments that provide motivational support for improved adherence to training activities in the mental health care field, which includes depression and other mental illnesses, like dementia and further brain‐related disorders as well as learning disorders.
Distinct immune signatures associated with sex and genotype in the 15m novel hAPP+hAPOE mouse risk model of Alzheimer’s disease
Authors: Delatorre Nicole , Van Rossum Hannah , Brinton Roberta Diaz 
Published: December 2023

AbstractBackgroundAlzheimer’s disease research continues to struggle with the translatability of animal models to human patients. Exploring whole systems is integral to early AD biomarker discovery in the pursuit of therapeutics to delay or prevent AD. Previous finds in our lab indicate sex differences in immune transcription levels in human AD brain and in the humanized apolipoprotein E (APOE) mouse model. Herein we investigated the impact of the APOE genotype in a novel mouse model, humanized amyloid precursor protein (APP), and humanized APOE transgenes (Jackson Laboratory).MethodsTo identify immunophenotypes at late‐midlife (15 months: late 40s – early 50s human correlative) a novel hAPP+hAPOE mouse model was utilized: hAPP (5M:5F), hAPP+hAPOE ε3/3 (16M:16F), & hAPP+hAPOE ε4/4 (16M:16F). The brain was hemisected. The left side was processed for multi‐color flow cytometry analysis. Peripheral blood was taken via cardiac puncture. The plasma was isolated and ELISA was used to detect levels of Aβ 40‐42 and pro‐inflammatory cytokines. PBMCs were isolated from the peripheral blood for multi‐color flow cytometry analysis. Microglia (CD45, CD11b), microglia reactivity (MHCII, CD68), phagocytosis (pHrodo), and oxidative stress (CellRox) levels were determined in the brain. Lymphocytes (CD3, CD4, CD8, CD19), lymphocyte activity (CD69), and oxidative stress (CellRox) levels were determined in both the brain and peripheral blood. Midlife endocrine status was determined for the female mice by daily lavage.ResultshAPP+hAPOE ε4/4 animals exhibited accelerated endocrine aging evidence by increased proportion of irregular cycling mice, compared to hAPP hAPOE ε3/3 animals. Microglial activation marker by MHCII was significantly impacted by sex (p<0.0001) and less so by genotype (p = 0.0551). Microglial function measured by pHrodo was impacted by sex (p<0.0001) with hAPP+hAPOE ε3/3 males exhibiting greater phagocytosis in MHCII+ microglia relative to their female counterpart.ConclusionThe interaction between the genotypes APP and APOE in combination with sex has a significant impact on immune phenotypes in the late‐midlife brain. These indications offer unique insights for future targeted therapeutics. Our findings support further investigation into neuroimmune activation in mid‐life to delay or prevent AD.
Using spatial transcriptomics to investigate region‐specific gene expression in J20 mice
Authors: Sander Millie , Brown Jonathan T , Lunnon Katie , Ballard Clive G 
Published: December 2023

AbstractBackgroundAlzheimer’s disease (AD) and dementia with Lewy bodies (DLB) share various pathological and symptomatic traits. As such, providing an accurate diagnosis of DLB can be difficult, ultimately impacting patient support and care. It is therefore imperative to establish biomarkers which reliably differentiate between disease states. Plasma‐derived exosomes appear to be promising in this regard. Exosomes are extracellular vesicles, containing cargos from the cell from which they originate. Increased concentrations of exosomal disease‐associated proteins, such as p‐T181‐tau and Aβ‐42, have previously been associated with cognitive decline and disease progression among AD patients (Winston et al., 2016; Kapogiannis et al., 2019).MethodWe aim to quantify exosome‐associated proteins from AD patients, DLB patients and healthy controls in order to establish exosomal signatures to differentiate between disease states. Exosomes are being isolated using differential ultracentrifugation. Nanoparticle track analysis (NTA) and western blots are being used to verify isolation, and ELISA assays against p‐T181‐tau, Aβ‐42 and α‐synuclein will be used to quantify proteins of interest. Plasma samples are being collected at baseline and after a 6 month follow‐up period in order to monitor the stability of these potential biomarkers.ResultTo date, full ethics approval has been granted for this study, and the differential ultracentrifugation protocol has been established. Successful isolation of particles in the size range of exosomes (30 – 100nm) has been confirmed using NTA. ELISA assays will be undertaken in the up‐coming months, with the aim of collecting and analysing baseline results by May 2023.ConclusionExosomes already appear to be a reliable, and relatively non‐invasive biomarker for assessing disease state and progression among dementia patients. Our preliminary findings have shown successful isolation, and we believe the findings could be invaluable with regards to improved diagnosis options for DLB.References:Kapogiannis, D. et al. (2019) ‘Association of Extracellular Vesicle Biomarkers With Alzheimer Disease in the Baltimore Longitudinal Study of Aging’, JAMA Neurology. https://doi.org/10.1001/jamaneurol.2019.2462Winston, C. N. et al. (2016) ‘Prediction of conversion from mild cognitive impairment to dementia with neuronally derived blood exosome protein profile’, Alzheimer’s and Dementia: Diagnosis, Assessment and Disease Monitoring. Elsevier Inc., 3, pp. 63‐72. https://doi.org/10.1016/j.dadm.2016.04.001.
Astrocyte reactivity is associated with synaptic dysfunction across the aging and Alzheimer’s disease spectrum, whereas microglial reactivity is specifically associated with synaptic dysfunction related to cognitive impairment
Authors: Rohden Francieli , Ferreira Pamela C.L. , Bellaver Bruna , Aguzzoli Cristiano Schaffer , Soares Carolina , Povala Guilherme , Ferrari‐Souza João Pedro , Lussier Firoza Z , Zalzale Hussein , Abbas Sarah , Lemaire Peter Charles , Leffa Douglas Teixeira , Cabrera Arlec , Tissot Cécile , Therriault Joseph , Servaes Stijn , Stevenson Jenna , Rahmouni Nesrine , Benedet Andrea Lessa , Cohen Annie , Lopez Oscar L. , Ashton Nicholas J. , Karikari Thomas K , Zetterberg Henrik , Blennow Kaj , Souza Diogo O. , Zimmer Eduardo R , Rosa‐Neto Pedro , Pascoal Tharick A. 
Published: December 2023

AbstractBackgroundHealthy synapses are the key to proper brain function, ensuring communication between neurons. Recent studies have associated synaptic dysfunction with Alzheimer’s disease (AD) proteins, however, little is known about the role of glial reactivity, another pathology closely linked to AD, in brain synaptic dysfunction (Figure 1).MethodWe evaluated 123 individuals (67 cognitively unimpaired (CU) and 56 cognitively impaired (CI)) who had available Aβ‐ and Tau‐PET as well as cerebrospinal fluid measures of glial fibrillary acidic protein (GFAP), chitinase‐3‐like protein 1 (YKL‐40), soluble triggering receptor expressed on myeloid cells 2 (sTREM2), synaptic markers (growth‐associated protein 43 (GAP‐43), neurogranin (Ng), synaptotagmin 1 (SYT1), and presynaptic protein synaptosomal‐associated protein 25 (SNAP‐25)). ANCOVA adjusted for clinical diagnosis, age, and sex was used to compare levels of CSF biomarkers; whereas linear regressions adjusted for age, sex, clinical diagnosis, and Aβ/tau‐PET were used to test the associations between glial reactivity and synaptic markers.ResultDemographic information is shown in Table 1. Increased levels of GAP‐43, SNAP‐25, and Ng were observed in CI compared to CU individuals. CSF GFAP was highly associated with both presynaptic and postsynaptic biomarkers in CU and CI groups. CSF YKL‐40 was associated only with presynaptic biomarkers in both clinical groups. On the other hand, CSF sTREM2 showed an association with all synaptic markers but only in the CI group (Figure 2).ConclusionWe found a heterogeneous association between synaptic markers and glial activation. The presence of GFAP+ astrocytes was associated with dysfunction of presynaptic/postsynaptic markers, whereas YKL‐40+ astrocytes specifically reflected presynaptic dysfunction across aging and AD spectrums. On the other hand, microglial activation reflected synaptic dysfunction associated with dementia symptoms. Our results support recent experimental observations suggesting that clarifying the heterogeneity of different glial cell phenotypes is crucial to advancing our understanding of the role of immune cells in cognitive decline.
The auditory phenotype of behavioural variant frontotemporal dementia
Authors: Johnson Jeremy , Levett Benjamin , Requena‐Komuro Mai‐Carmen , Benhamou Elia , Jiang Jessica , Bamiou Doris‐Eva , Hardy Chris JD , Warren Jason D 
Published: December 2023

AbstractBackgroundPatients with behavioural variant frontotemporal dementia commonly exhibit abnormal hedonic and other behavioural responses to sounds, however hearing dysfunction in this disorder is poorly characterised. Here we addressed this issue using the Queen Square Tests of Auditory Cognition (QSTAC) – a neuropsychological battery for the systematic assessment of central auditory functions (including pitch pattern perception, environmental sound recognition, sound localisation and emotion processing) in cognitively impaired people.MethodThe QSTAC was administered to 15 patients with behavioural variant frontotempoal dementia, 24 patients with comparator dementia syndromes (primary progressive aphasia and typical Alzheimer’s disease) and 15 healthy age‐matched individuals. Participants also had pure tone audiometry to assess peripheral hearing function and a comprehensive general neuropsychological assessment.ResultAfter accounting for nonverbal executive and peripheral hearing performance, patients with behavioural variant frontotemporal dementia showed deficits of environmental sound and auditory emotion recognition and sound localisation, compared both with healthy controls and patients with Alzheimer’s disease. Patients with behavioural variant frontotemporal dementia were further differentiated from primary progressive aphasia patients on their performance across QSTAC (sound recognition and localisation) subtests.ConclusionBehavioural variant frontotemporal dementia has a distinct phenotype of auditory cognitive dysfunction which likely contributes to the hearing alterations that many patients with this diagnosis experience in daily life. Our findings call attention to an under‐recognised issue in frontotemporal dementia that warrants further clinical interpretation and the development of management strategies tailored to real‐world acoustic environments.