bluuebunny/crossref_metadata_2025_split huggingface dataset:
The effect of hippocampal cis‐p tau injection in learning and memory and synaptic plasticity
Authors: Bakhtiarzadeh Fatemeh , Shahpasand Koroosh , Najafi_Zadeh Javad Mir 
Published: December 2020

AbstractBackgroundExperimental models of Alzheimer’s disease (AD) are critical to gaining a better understanding of pathogenesis and to assess the potential of novel therapeutic approaches. The aim of this study is to introduce a new model for AD.MethodMale C57BL/6 (3‐6 months) were divided into three groups: control, sham and cis‐p tau groups. We injected 2 µg/µl cis‐p tau or its vehicle bilaterally into the hippocampal CA1 region. Short term memory assessed (by Y‐maze test) and spatial learning and memory (by Barnes maze test were evaluated. In vitro field potential recordings were done in all three groups. Primed‐burst stimulation (PBS) protocol was applied to induce long‐term potentiation.ResultHippocampal injection of cis‐p tau significantly decreased spontaneous alternation 14 days and one month (p<0.001) and 4 months (p<0.05) after injection. One month after cis‐p tau injection, primary and scape latency and also primary and total error increased in Barnes maze test (p<0.05) but not at 14 days and 4 months after injection. Field potential recording showed that hippocampal injection of cis‐p tau significantly (p<0.01) disrupted maintenance of LTP in dorsal hippocampal region but had no effect on ventral region both one month and four months after the injection.ConclusionCis‐p tau injection as a new model of Alzheimer’s‐like disease decreased short term memory, learning and spatial memory. Bilaterally injection of cis‐p tau impaired long term potentiation and synaptic plasticity in dorsal region of CA1 hippocampal area.
Salvaging COVID‐19 interrupted Alzheimer clinical trials using virtual patient simulations
Authors: Geerts Hugo , Van der Graaf Piet 
Published: December 2020

AbstractBackgroundThe COVID‐19 pandemic has halted many Alzheimer’s Disease clinical trials, with some forced to re‐start at different points along the trial time‐line with substantial protocol amendments and patients dropping out with substantial partial assessments. To align the functional outcomes of these protocol amendments with the original trial design at the individual patient level, we propose to use Physiology‐Based Pharmacokinetic (PBPK) and Quantitative Systems Pharmacology (QSP) Modeling to ‘correct’ the cognitive trajectory of mirror virtual patient population back to the original trail design.MethodThe Virtual Twin approach creates a PBPK computer‐simulated model of each patient with a virtual twin QSP model of trial subjects, with the same co‐medications, common genotype variants affecting metabolism and cognitive outcome; β‐amyloid and tau biomarkers. The QSP platform is a previously ADAS‐Cog calibrated model of key neuronal circuits involved in cognition, allowing to model the effects of CNS active co‐medications based on their pharmacology and genotypes based on imaging studies. In this Virtual Twin approach, the platform will be extensively validated against the actual clinical data from the completer set and the fragmented outcomes of the restarters with their individual protocol amendments, before simulating the cognitive trajectory with the original trial design for those whose trial was interrupted.ResultDifferent interruption scenarios in a 24‐month AD study of a bi‐weekly amyloid antibody infusion are simulated with increased anxiolytics and anti‐depressants use after restart. The impact of changes is dependent upon the genotype combination with the 5‐HTTLPR rs 23351 > APOE > COMTVal158Met and different for placebo and active treatment. Anti‐depressants and benzo also differentially substantially affect the cognitive trajectory. We illustrate how to reconstruct the cognitive trajectory of 600 subjects (out of 1200) affected by the interruption.ConclusionCombining QSP modeling of the biology with PBPK modeling and extensive validation with the fragmented clinical data available, in principle allows to reconstruct the original cognitive trajectory in patients affected by the COVID‐19 interruption. In this way, the original trial design and statistical analysis plan can be applied to achieve a fair evaluation of the clinical effect of the investigative new drug.
Implementing an arts‐based recreation program for older adults in care settings
Authors: Swaminathan Swathi , Altschuler Aviva , Howard Elizabeth P , Hasher Lynn , Murphy Kelly J 
Published: December 2020

AbstractBackgroundResearch shows that older adults with memory‐support and complex‐care needs can meaningfully benefit from arts‐based activities because it can make them feel good, promote their sense of connection with personal and community identity, and stimulate thinking and memory. As a result, there is growing interest in integrating participatory arts techniques in clinical care settings. In this qualitative study, we explore therapeutic recreationists’ (TRs) experiences of implementing a visual‐arts program designed to promote learning and creative engagement.MethodParticipants were eight TRs or TR interns working in long‐term care (n = 4), short‐term residential (complex and palliative) care (n = 3), or memory day‐clinic (n = 1) settings. All implemented an arts‐based recreation program, ArtontheBrain, for at least 12 sessions over 6 weeks to older adults in their care in one‐on‐one or group sessions. ArtontheBrain is a virtual platform that delivers visual‐art content with modules designed to facilitate learning, play and storytelling (both reminiscence and imagined stories). TRs were encouraged to flexibly implement ArtontheBrain according to their judgement of how to best engage clients. TRs completed semi‐structured interviews which were then thematically analysed using NVivo 12 software.ResultEmergent themes revealed that TRs were able to effectively use the arts‐based activity to (1) provide stimulating and appropriately paced cognitive challenges, (2) facilitate reminiscence and imagination, (3) promote conversation and social interaction, (4) learn new information about their clients’ preserved skills and interests, and (5) learn new facts about the world from their clients.ConclusionTRs found the arts‐based program to be a useful addition to their existing suite of care techniques. This finding complements results of studies documenting that older adults in care find arts‐based programs to be valuable in promoting their sense of wellbeing. Future research could investigate questions of who is likely to benefit from arts‐based programs and what methods are most effective for implementing arts‐based programs for older adults in care settings.
Tyramine and amyloid beta 42: A toxic synergy
Authors: Dhakal Sudip , Macreadie Ian George 
Published: December 2020

AbstractBackgroundIn synaptic cleft, trace amines play a crucial role as neurotransmitter signaling through the trace amine associated receptors. Tyramine, an important trace amine formed by decarboxylation of tyrosine, has been reported to be implicated in various diseases including schizophrenia, Parkinson's disease, migraine and Huntington's disease. However, there are no investigations to find its connection with Alzheimer's disease (AD).MethodGenetically modified Saccharomyces cerevisiae BY4743 producing different forms of amyloid beta 42 (Aβ42) peptide including native Aβ42 and green fluorescent protein (GFP) fused to Aβ42 were treated with various concentrations of tyramine. Reactive oxygen species (ROS) produced in these strains were measured using 2′,7′‐dichlorodihydrofluorescein diacetate (H2DCF‐DA) staining in a flow cytometric analysis. Growth inhibition of the yeast strains producing GFP and GFP‐Aβ42 were analysed in presence of tyramine. Petites generated due to tyramine were estimated in both these strains and petite frequency calculated.ResultTyramine was found to induce ROS formation in S. cerevisiae BY4743 as well as its genetically modified variants. ROS formation in yeast strains producing native Aβ42 treated with tyramine was significantly synergistically higher as compared to experimental controls. Similarly, yeast strains producing GFP‐Aβ42 was found to be inhibited more in media containing ethanol as sole carbon source compared to GFP producing controls in presence of 3 mM tyramine. Additionally, petite frequency in yeast strains producing GFP‐Aβ42 were found to increase significantly from around 20% to nearly 80% when grown in presence of tyramine.ConclusionThese findings suggest that tyramine in presence of Aβ42 is synergistically toxic to yeast cells by inducing ROS formation and causing petite mutation, implying possible cause of mitochondrial damage evident in AD patients. The study also demonstrates yeast as model to study compounds that have potential to exacerbate AD.
Chronic renal function impairment‐induced cognitive changes and related pathology in mice after unilateral ureteral obstruction (UUO) surgery
Authors: Ho Janice Yuen Shan , Lau Chi‐Fai , Tang Wing‐Yan , Tian Jia‐Yan , Lee Joyce , Yung Susan Sou‐Ying , Chang Raymond Chuen‐Chung 
Published: December 2020

AbstractBackgroundChronic kidney disease is associated with cognitive impairment. While the pathophysiology remains unclear, it has been suggested that it shares some similarity to those in Alzheimer’s disease. Currently, most studies in this area used the 5/6 nephrectomy and high adenine diet to induce renal impairment in rat or mice. Our group had successfully used the unilateral ureteral obstruction (UUO) mice as an animal model to study the cognitive changes and related pathology.MethodEight‐week‐old male C57BL/6N mice received the UUO operation with double ligation of their left ureter under general anesthesia. Sham operated mice received the same experimental procedure without ureteral obstruction. Cognitive and behavioral tests were performed to examine potential changes in cognition and other behavior 2, 4 or 12 weeks after the surgery. The serum, kidneys and brains were harvested for the detection of systematic inflammation markers and neurodegenerative changes.ResultProgressive renal impairment were observed after the UUO surgery. Systematic inflammation was evident by detecting an increase in C‐reactive protein and TNF‐a levels in the UUO mice. These mice also showed a significantly worse performance in the novel object recognition test, Y‐maze test, and puzzle box test when compared to the sham control, indicated cognitive impairment. Reduction in synaptic proteins such as synapsin‐1, synaptophysin, synaptotagmin, PSD95, NMDAR2B and AMPAR, elevation of Nrf2 and 8‐Hydroxyguanosine and hyperphosphorylation of tau were found in their hippocampus.ConclusionWe have characterized the cognitive and neuropathological changes in the UUO mice. This mouse model can be used for studying chronic kidney disease‐induced cognitive impairment and may have an implication for understanding the pathogenesis of Alzheimer’s disease.
Glial control of the local translatome in AD
Authors: Gamarra María , Blanco‐Urrejola Maite , Baleriola Jimena 
Published: December 2020

AbstractBackgroundUnder pathological conditions axons respond to Aβ oligomers by increasing localized translation which in turn contributes to neurodegeneration. Additionally, a link between intra‐dendritic translation, and Tau mislocalization and hyperphosphorilation has been found. Thus, dysregulation of local protein synthesis in neurons seems to play a relevant role in AD. Although local translation has been recently become accepted, there are several aspects of this phenomenon that are still under debate. It is unclear whether local protein synthesis is fully cell‐autonomously regulated or if it relies upon non‐neuronal cells surrounding the neurons. Our laboratory aims at deciphering the contribution of glia to local neuronal translation in physiological and Aβ‐induced pathological conditions.MethodWe performed neuron and neuron‐astroglia cultures on coverslips or on Boyden chambers to address the effect of glia on local translation. Cultures were treated with vehicle or Aβ. Boyden chambers were used for proteomic analyses of soma and neuritic extracts when cells were cultured with or without astrocytes and treated with vehicle or Aβ. Extracted samples were subjected to LC‐MS/MS and gene ontology analysis was performed with DAVID. Finally, we have addressed whether extracellular vesicles (EVs) play a role in local translation. EVs secreted by cells treated with vehicle or Aβ were isolated by ultracentrifugation. EVs or EV‐depleted media were used to treat naïve neurons and local translation was measured.ResultCultures on coverslips and in Boyden chambers revealed that secreted factors in the presence of astrocytes increase protein synthesis in control and Aβ‐treated neurites. We have identified 72 significantly‐regulated proteins in Aβ‐treated neurons compared to controls in the absence of astrocytes, whereas 55 proteins were significantly changed in Aβ‐treated vs controls in neuron‐astrocyte co‐cultures. Only 4 proteins were common to both cultures, suggesting that the presence of astrocytes dramatically changes the local proteome upon Aβ treatment. Finally, our experiments suggest that glial EVs distinctly regulate local protein synthesis in neurons in physiological and pathological conditions.ConclusionAstrocytes play a key role in the regulation of protein synthesis in neurites in both physiological and pathological conditions. Moreover, our results suggest that glia mediates its effect on neurites through EV release.
Glial cells derived from pluripotent stem cells as a suitable tool for modeling Alzheimer’s disease
Authors: Leon Juan Antonio Garcia , Palomo Laura Caceres , Davila Jose Carlos , Vitorica Javier , Gutierrez Antonia 
Published: December 2020

AbstractBackgroundAlzheimer's disease (AD) is characterized by presenting a complex pathology, not fully resolved yet. This fact, together with the lack of reliable models, has impeded the development of effective therapies. Recently, several studies have shown that functional glial cell defects have a key role in the pathology of AD. However, this glial dysfunction, currently, cannot be correctly modeled using the available animal models, so we hypothesized that cells derived from Alzheimer's patients can serve as a better platform for studying the disease. In this sense, human pluripotent stem cells (hPSC) allow the generation of different types of neural cells, which can be used for disease modeling, identification of new targets and drugs development.MethodWe have a collection of hiPSCs derived from patients with sporadic forms of AD. We have differentiated these cells towards neural lineage to obtain neurons and astrocytes. For the generation of oligodendrocytes (OLs), we have developed a fast and robust protocol to generate mature OLs in just 22 days.ResultWe have generated neural precursors from all the lines tested. In the case of OLs, the cells generated resemble primary OLs and can myelinate neurons in vivo and in vitro using a screening compatible platform. This platform is being transferred for the generation of the other glial cells.ConclusionThis methodology can be used to elucidate the pathogenic pathways associated with neurodegeneration and to identify new therapeutic targets susceptible to modulation, contributing to the development of new effective drugs against AD. Acknowledgments: J.A.G.L has been supported by a contract of doctor reincorporation plan from the I Plan Propio of the University of Malaga (Spain) and by CIBERNED. The work was supported by Instituto de Salud Carlos III (ISCiii) of Spain, co‐financed by FEDER funds from European Union (grant PI18/01557 to A.G., grant P18/1556 to JV), by Junta de Andalucia co‐financed by FEDER funds grant UMA18‐FEDERJA‐211 (to AG), by Consejeria de Salud of Junta de Andalucia (grant PI‐0276‐2018 to J.A.G.L.) and by CIBERNED.
Plasma p‐tau181 accurately predicts Alzheimer’s disease pathology at least 8 years prior to post‐mortem and improves the clinical characterisation of cognitive decline
Authors: Rodriguez Juan Lantero , Karikari Thomas K , Suárez‐Calvet Marc , Troakes Claire , King Andrew , Emeršič Andreja , Aarsland Dag , Hye Abdul , Zetterberg Henrik , Blennow Kaj , Ashton Nicholas J 
Published: December 2020

AbstractBackgroundNowadays, Alzheimer’s disease (AD) can be diagnosed in vivo using both cerebrospinal fluid (CSF) and positron emission tomography (PET) biomarkers. Although highly accurate, their broad implementation has been impeded due to limitations including high cost, perceived invasiveness and limited availability. Thus, much effort has been placed in the discovery of blood biomarkers. In this context, our high performance blood immunoassay for p‐tau181 has already showed an excellent ability to specifically identify AD. Therefore, the aim of this study was to investigate if plasma p‐tau181 reflects AD pathology in post‐mortem confirmed cases and if this biomarker can successfully discriminate AD from non‐AD dementia pathologies.MethodUsing our plasma p‐tau181 assay, we studied a unique cohort of 115 individuals selected from the Maudsley and King's Healthcare Partners Dementia Case Register, which incorporates the Alzheimer's Research UK cohort. The cohort included longitudinal plasma collections and clinical evaluation at 8, 4 and 2 years followed by neuropathological examination after death.ResultOur results demonstrate that plasma p‐tau181 accurately predicts AD pathology and Braak staging at least 8 years before death. Moreover, plasma p‐tau181 proved to accurately discriminate AD from non‐AD pathologies (AUC=97.5%, 95% CI=94.1‐100%). This strongly suggests that a clinical diagnosis of AD dementia combined with low plasma p‐tau181 levels would be useful to identify non‐AD pathology. Additionally, we described the longitudinal trajectory of plasma p‐tau181 in AD patients. We found that the main increase in plasma p‐tau181 levels occurred between 8 and 4 years before death, and later plateaus.ConclusionAltogether, our results demonstrate that plasma p‐tau181 is highly specific and predictive of AD pathology several years before neuropathological examination. Moreover, these results strongly support the implementation of plasma p‐tau181 in clinical diagnosis, longitudinal monitoring and therapeutic trial recruitment.
Mitochondrial DNA copy number is associated with cognitive impairment
Authors: Andrews Shea J , Goate Alison M 
Published: December 2020

AbstractBackgroundIncreasing evidence has implicated mitochondrial dysfunction in the pathogenesis of Alzheimer’s Disease. Mitochondria contain their own DNA outside of the nuclear genome, with every cell having between 100‐10,000 copies of mtDNA. Mitochondrial DNA copy number (mtDNAcn) has been used as a surrogate measure of mitochondrial function, with reduced mtDNAcn associated with age‐related diseases. The aim of this study was to evaluate the association of mtDNAcn with cognitive impairment.MethodsWe evaluated the association of mtDNAcn with the extended Clinical Dementia Rating (CDR) scale in the Mount Sinai Brain Bank (MSBB) and with mini mental state exam (MMSE) in the Religious Orders Studies and the Memory Aging Project (ROSMAP). Relative mtDNAcn was estimated as the ratio of mitochondrial genomes to nuclear genomes in 1025 non‐Hispanic white subjects (MSBB = 277; ROSMAP = 748) using whole‐genome sequencing data generated from DNA isolated from post‐mortem brain tissue (MSBB: prefrontal cortex; ROSMAP: dorsolateral prefrontal cortex [DLPFC], posterior cingulate cortex [PCC], or cerebellum). Linear regression adjusting for age of death, sex, APOE, study, mitochondrial haplogroup and source tissue were used to evaluate the association of mtDNAcn with cognitive impairment.ResultsIn the MSBB, a one standard deviation decrease (1 s.d. 343) in mtDNAcn was associated with a higher CDR score (b(se) = 0.71 (0.10), p = 3.41e‐12, Fig. 1). Similarly, in ROSMAP a one standard deviation decrease (1 s.d. 1063) in mtDNAcn was associated with a lower MMSE score (b(se) = ‐4.02 (0.75), p = 1.07e‐7, Fig. 2).ConclusionMitochondrial dysfunction as measured by mtDNAcn is associated with worse cognitive performance, suggesting that mitochondrial function plays a role in the pathogenesis of Alzheimer’s Disease. However, further research is needed to determine if mitochondrial dysfunction causes, mediates, or is a by‐product of AD pathogenesis, in particular whether neuronal loss is an unobserved confounder that could be driving the observed associations.
Delivery of CANTAB assessments across diverse health systems
Authors: Baker Elizabeth , Dente Pasquale , Backx Rosa , Lowther Millie , Cotter Jack , Cormack Francesca K , Barnett Jenny 
Published: December 2020

AbstractBackgroundAssessment of cognitive function is an important component of differential diagnosis in Alzheimer’s disease and dementia and is critical to characterising the impact of the disease. Objective assessment of function provides real world evidence for assessing effectiveness of current standards of care, and evaluating interventions designed to improve outcomes. However, sensitive, reliable tools for administering standardised tests at scale have been lacking to date.MethodDigital tools, providing near‐patient assessments in the community or at home are one way to meet the demands of patient characterisation across a range of resource settings. Cambridge Neuropsychological Automated Test Battery (CANTAB) is a set of 25 computerised assessments designed to assess cognition across a broad range of domains relevant to neurological and psychiatric conditions. A number of tests from this battery have been integrated into medical device software to assess the impact of neurological and neurodegenerative disease. These tools have been deployed in community, primary and secondary health care settings in relatively resource‐rich healthcare systems (primarily UK and US). We are exploring whether such an approach can be generalised to a lower‐middle income countries/South Asia.ResultWe will present performance of 4000 healthy participants recruited across nine regions of India on CANTAB assessments including performance on episodic memory (Paired Associates Learning (PAL)), working memory (Spatial Working Memory (SWM)) and attention (Matching to Sample (MTS)). Evidence from this study supports the suitability of our platform for delivering cognitive assessments in health care systems outside the UK. We will contrast performance of healthy participants on PAL and SWM with recent normative data collections across the UK and US; demonstrating similarity of performance and the effectiveness of assessment platforms. The demographic diversity of these normative collections supports the need to partner these tools with appropriate recruitment and operational initiatives to ensure accessibility.ConclusionWe will reflect on how this evidence guides our current and future plans for making scientifically robust cognitive assessment tools globally available, both for increasing access to treatment, but also in the context of basic research and drug development.