bluuebunny/crossref_metadata_2025_split huggingface dataset:
Investigating 4R tau isoform imbalance as a mediator of astrocyte dysfunction in tauopathies
Authors: Schoch Kathleen M. , Ezerskiy Lubov A. , Hu Miwei , Beltcheva Mariana , Rigo Frank , Miller Timothy M. 
Published: December 2023

AbstractBackgroundSelect primary tauopathies exhibit MAPT (tau) mis‐splicing to produce an imbalance of 3R and 4R tau isoforms. Further, 3R and 4R tau isoforms deposit in neurons and glia in tauopathy patients, although it remains unclear whether tau isoform deposition is a cause or consequence of disease. Our group and others have identified a role for 4R tau in increased tau phosphorylation and aggregation, suggesting that 4R tau‐mediated mechanisms may influence disease. Therefore, therapeutic strategies targeted against 4R tau may be beneficial.MethodWe developed antisense oligonucleotides (ASOs) that enable control of 3R and 4R tau splicing without altering total tau levels in human tau‐expressing mice, primary mouse astrocytes, and astrocytes derived from human induced pluripotent stem cells (iPSCs). We quantified gene markers of astrocyte reactivity and measures of astrocyte function, including glutamate uptake and response to oxidative stress. Finally, we performed bulk RNAseq from mouse brain tissue following tau splicing manipulation.ResultIncreasing 4R tau in human tau mice and primary mouse astrocytes induced a neurotoxic gene signature, including evidence for complement pathway involvement. Astrocytes derived from iPSCs of tauopathy patients expressing the MAPT mutation IVS 10+16 (biases toward 4R tau expression) exhibited increased expression of genes associated with neurotoxicity, were vulnerable to oxidative stress, and had reduced glutamate uptake. 4R tau‐expressing astrocytes, including IVS 10+16 mutation carriers, promoted hyperexcitability characteristics in co‐cultured neurons compared to controls. Bulk RNAseq analysis supported isoform‐specific changes in gene expression.ConclusionAstrocytes appear particularly vulnerable to increased 4R tau in vivo and in vitro, inducing dysfunction that may leave neurons prone to hyperexcitability and degeneration. Although tau isoform imbalance toward greater 4R tau likely induces both neuronal and glial changes, tau‐mediated toxicity within astrocytes may reveal unique mechanisms of disease progression and targets for therapeutics.
The effect of vitamin D on neurite length and neurite elongation velocity during development
Authors: Keskin Ebru , Gezen‐Ak Duygu , Dursun Erdinc 
Published: December 2023

AbstractBackgroundStudies have shown that vitamin D plays an important role in the brain (1). In an animal model of nerve trauma, vitamin D2 (ergocalciferol) was shown to be a potent neuromodulatory compound that increases axogenesis, axon diameter, and physiological maturation (2). In addition, the administration of high‐dose vitamin D3 (cholecalciferol) has been demonstrated to enhance the number of preserved or newly formed axons at the proximal end, axon diameter at the distal end, and neurite myelination at both the distal and proximal ends in another animal model of nerve trauma (3). Vitamin D has been shown to increase neurite outgrowth when added to cultured hippocampal cells. However, when removed from the diet of pregnant rats, decreased expression of NGF (neuron growth factor (NGF) was observed in the brains of newborns and adults. Recently, vitamin D has been shown to increase the expression of microtubule‐associated protein‐2 (MAP2), axonal growth‐associated protein‐43 (GAP43), and synapsin‐1 protein in rat cortical neurons (4). Based on this knowledge, we sought to determine whether vitamin D treatment during development might affect neurite length, and elongation velocity.MethodIn our study, primary cortical neuron culture was performed using 16‐day‐old rat embryos. 10−8 M 1,25‐dihydroxyvitamin D3 was applied 24 hours after the culture. Following vitamin D administration, neurite length measurements were made at 30‐second intervals for 30 min and at half‐hour intervals for 12 h under a live cell imaging microscope at 20X magnification.ResultThe results of our study showed that 30 min after vitamin D administration, neurite length and elongation velocity significantly increased in the vitamin D group compared to the control group (p = 0.0029 and p = 0.0310, respectively). In addition, the neurite outgrowth rate and neurite length increased in the vitamin D group 12 h after vitamin D administration compared to the control group (p = 0.0275, p = 0.0398, respectively).ConclusionOnly a few research have examined at how vitamin D affects neurite outgrowth. As a result of vitamin D administration in primary cortical neurons during the developmental phase, our study’s results demonstrated that neurite length and velocity increase in the first 12 hours.
Altered brain connectivity, neuroinflammation and AD‐related markers following 7 days after repetitive mild traumatic brain injury in young wild‐type mice
Authors: Criado‐Marrero Marangelie , Ravi Sakthivel , Hery Gabriela P , Bolen Mackenzie L , Febo Marcelo , Grudny Matteo M , Prokop Stefan , Abisambra Jose F. F 
Published: December 2023

AbstractBackgroundTraumatic brain injuries (TBI) substantially increase the risk for neurodegenerative disorders including tauopathies and synucleinopathies. Repetitive mild TBI (rmTBI) exacerbate damage in brain impacting cognitive and emotional processes through lifetime. Therefore, there is a critical need to identify the molecular mechanisms underlying TBI‐mediated brain dysfunction. In doing so, we can develop effective therapies as the etiology for dementia remain poorly understood. Our goal is to identify early, unbiased, and novel biomarkers of brain dysfunction following rmTBI. These include defects in the brain connectome and protein expression in the areas most functionally susceptible to damage following rmTBI.MethodTo do this, we exposed young male and female C57BL/6J wild‐type mice to two rmTBI (2 × 0.6 J impacts/24 h apart) using the closed head injury model of engineered rotational acceleration (CHIMERA) or sham procedures. We measured changes in brain functional connectivity (FC) using resting state functional MRI (rsfMRI) and graph theory, examined microstructural differences in white and grey matter regions through diffusion tensor imaging (DTI) analyses, surveyed neuropathological proteins using NanoString‐GeoMx Digital spatial protein profiling spatial profiling (DSP).ResultThe rsfMRI data revealed that rmTBI induces aberrant changes in the graph metrics such as node clustering coefficient, global and local efficiency, participation coefficient, eigenvector centrality, and betweenness centrality in brain regions processing visual, auditory, and somatosensory information. The optic tract and thalamus were the most affected regions showing significant differences in phospho‐tau (S199), neuroinflammatory markers (GFAP, Iba‐1, GPNMB), and other proteolytic (cathepsin‐D) and proliferation (ki‐67) cell markers. We identified extensive white matter damage, defects in brain FC, and exacerbated anatomically distinct protein profiles.ConclusionThese findings align with results reported in individuals with TBI such as diffuse axonal damage, glial activation, and functional network disruption in the visual tract and specific thalamic regions. Upcoming studies will evaluate the potential use of using brain imaging along with molecular markers to predict longitudinal damage after rmTBI.
Immunotherapy against tau pathology in mouse models requires cytosolic Fc receptor TRIM21
Authors: McEwan Will 
Published: December 2023

AbstractBackgroundThe passive transfer of monoclonal antibodies reduces tau pathology in mouse models and is under evaluation as a potential immunotherapeutic strategy against Alzheimer’s disease and other tauopathies. The mechanisms that drive therapeutic protection of anti‐tau antibodies are not well understood.MethodP301S tau transgenic animals were treated with antibodies against pS422 and analysed for tau pathology by biochemical fractionation. Organotypic hippocampal slice cultures were used as a model of tau seeding and neutralisation. AAV serotypes were used to deliver tau‐selective degraders.ResultGenetic deletion of the cytosolic antibody receptor and E3 ubiquitin ligase TRIM21 rendered tau immunotherapy ineffective in animal models. In organotypic slices, expression of TRIM21 was essential for protection against seeded aggregation of tau. Cytosolic antibody‐tau complexes were visible inside neurons in complex with TRIM21 shortly after application of tau assemblies and antibodies to the cell exterior. Nanobody‐based degraders were developed using TRIM21 and found to protect against tau pathology.ConclusionAnti‐tau antibodies can engage extracellular tau seeds and enter neurons as a complex. Following cytosolic entry, TRIM21 engages the antibodies and mediates neutralisation of tau seeding activity. The results reveal a mechanism that can be optimised for future immunotherapeutics. In this direction, AAV‐delivered degraders reveal a route by which tau aggregates may be selectively removed from the brain.
Supporting Carer Partners of People with Dementia: A Study from Six Countries
Authors: Kinchin Irina , Adrion Emily R , Chen Yaohua Sophie , Dupont Charlèss , Mayan Inbal , Epenge Emmanuel , Almirall‐Sanchez Arianna ,   Economics of Dementia and Brain Health Special Interest Group at the Global Brain Health Institute
Published: December 2023

AbstractBackgroundDementia not only affects the person diagnosed, but also their family and wider support network. Care partners are often unpaid and untrained. They face financial, social, and psychological stressors that impact their health and wellbeing and may ultimately affect the quality of care. Easy and timely access to information, training, services, social and financial support throughout a caring trajectory are vital elements of a holistic support system. This study aims to assess dementia‐specific support and services in different countries and healthcare settings and map those against the needs of care partners.MethodsAn exploratory analysis of publicly available information on dementia‐specific support and services in six countries conveniently sampled, including Belgium, the Democratic Republic of Congo, France, Ireland, Israel, and the UK. A descriptive analysis of the data was performed by the number and type of services, sector, and accessibility. Support and services were subsequently mapped against the taxonomy of needs of care partners of people with dementia identified from the literature.ResultsPreliminary results revealed that all selected countries except the Democratic Republic of Congo exhibited publicly accessible information on dementia‐specific support and services available in the capital, main cities, and rural areas. The public and NGO were the most prevalent sector providing the support. Depth, detail, and location of information on available services varied across countries, in some instances requiring visits to multiple governmental, public sector or quasi‐public sector sites. Final results will be presented at AAIC 2023.ConclusionUnmet needs are not just an individual issue, but a phenomenon linked to social and economic disadvantage and societal inequality. The creation and implementation of means to deliver multisectoral care, support and services for carer partners of people with dementia to meet their unique needs and prevent a decline in physical and mental health and social wellbeing is warranted irrespective of the healthcare setting, but particularly so in low‐ and middle‐income settings.
The effectiveness of the glucagon‐like peptide 1 receptor agonist in improving cognitive function
Authors: Rasmussen Naoise , Burns Richéal , Coughlan Karen 
Published: December 2023

AbstractBackgroundRecent evidence suggests that glucagon‐like peptide 1 receptor agonists, commonly used to treat diabetes and obesity (Norgaard, 2022), are neuroprotective (Cheng, 2022), which may result in an improvement in cognitive function (Norgaard, 2022). The aim of this review is to determine the potential effectiveness of glucagon‐like peptide 1 receptor agonist therapy at improving cognitive function in a human population in literature published thus far.MethodSearches for applicable studies were conducted on PubMed, Cochrane library, Google scholar, CINAHL and Clinical Trials.gov. Studies which compare the efficacy of the glucagon‐like peptide 1 receptor agonist to placebo were included. The main outcome is the change in cognitive function assessed via cognitive testing. Data was expressed as mean difference/hazard ratio and corresponding 95% confidence interval. Quality assessment was conducted with the Cochrane risk of bias tool for randomized trials (RoB 2). Heterogeneity was assessed with the chi‐squared test and I2 statistic. The study was registered on PROSPERO (ID: CRD42022366254).ResultA total of n = 11,424 studies were identified for this review. After the removal of duplicates and the application of eligibility criteria, five studies (comprising n = 8,950 individuals) were included. Risk of bias across the included studies was low. Only one study reported an improvement in cognitive function associated with glucagon‐like peptide 1 receptor agonists. The results of the meta‐analysis inclusive of the five studies are inconclusive.ConclusionOverall, four of the five included studies were hampered by short drug duration times and small population sizes, which may have impacted the final result and conclusion. There is an urgent need for therapies to improve cognitive function, due to the rapid rise in cognitive decline worldwide. Glucagon‐like peptide 1 receptor agonists may fill this need, although further research is warranted.Cheng. (2022). The Role of Glucagon‐Like Peptide‐1 Receptor Agonists (GLP‐1 RA) in Diabetes‐Related Neurodegenerative Diseases. Drug Des Devel Ther, 16: 665‐684.Norgaard. (2022). Treatment with glucagon‐like peptide‐1 receptor agonists and incidence of dementia: Data from pooled double‐blind randomized controlled trials and nationwide disease and prescription registers. Alzheimers Dement (N.Y), 8(1):e12268.
In vivo safety and efficacy of a CRISPR‐based gene therapy for Alzheimer’s disease
Authors: Aulston Brent D , Branes Kristen , Checka Nidhi , Parra‐Rivas Leonardo A , Roy Subhojit 
Published: December 2023

AbstractBackgroundOur lab has developed a gene‐editing strategy to target the extreme C‐terminus (C‐term) of APP (amyloid precursor protein) – a gene with a central and indisputable role in AD. In physiologic states, the APP protein is cleaved by α‐secretases to generate neuroprotective sAPPα; but in AD (both sporadic and familial), the alternative β‐cleavage pathway is active, generating pathologic fragments (including Aβ). Specifically, our approach attenuates pathologic β‐cleavage products by disrupting a pentapeptide “YENPTY” domain at the APP C‐term, and this retains the edited APP (APP‐ΔC) at the cell‐surface, augmenting neuroprotective and neuroregenerative α‐cleavage.MethodIn order to assess the safety and efficacy of our approach in vivo, we used two different CRISPR‐editing approaches. First, we generated germline edits in Wt and APP knockin (APPNL‐G‐F) mice by injecting embryos with APP C‐term targeting CRISPRs. We then selected founders to produce stable strains of WT and APP‐KI in which the APP C‐term was genomically deleted (referred to as WtΔC and KI‐ΔC mice respectively). In another set of experiments, we packaged APP C‐term CRISPRs into AAV vectors and systemically injected AAVs into APP‐KI mice.ResultWtΔC showed no cognitive deficits or histological abnormalities compared to Wt controls. KI‐ΔC showed a dramatic reduction of amyloid beta plaques and associated neuroinflammatory markers and similar results were observed in AAV‐treated KI mice. Moreover, both germline and somatic APP C‐term editing produced an increase in neuroprotective sAPPα.ConclusionIn total, these data demonstrate that our approach is safe and efficacious in vivo and validate the feasibility of our APP C‐terminus editing approach as a therapeutic for AD.
The association between diabetes measures and Alzheimer’s disease biomarkers in CSF – A meta‐analysis
Authors: van Gils Veerle , Rizzo Marianna , Côte Jade , Viechtbauer Wolfgang , Visser Pieter Jelle , Jansen Willemijn J. , Vos Stephanie J. B. ,   the PRIME consortium
Published: December 2023

AbstractBackgroundDiabetes and blood glucose markers have previously been linked to cognitive decline. However, findings on the relation of diabetes with underlying Alzheimer’s disease (AD) biomarkers are inconclusive. We aimed to explore whether diabetes and blood glucose markers are associated with AD biomarkers in cerebrospinal fluid (CSF) by performing a meta‐analysis of existing studies.MethodA systematic search in PubMed and Embase with abstract and full‐text screening resulted in the inclusion of 13 studies with 5,052 participants in our meta‐analysis. We included studies that provided results on the association between a diabetes measure and an AD biomarker in CSF (Table 1). Diabetes measures included diabetes diagnosis or glucose measures, i.e. fasting blood glucose, HbA1c, or insulin resistance index. AD biomarkers included CSF amyloid‐beta42, p‐tau and/or t‐tau. Where needed, results were converted to partial or biserial correlation coefficients. We performed a random effects meta‐analysis on the correlation coefficients per CSF biomarker, using the DerSimonian and Laird procedure and Knapp‐Hartung method. Meta‐regression was used to test potential moderating effects of age, sex, setting (memory clinic or population), % dementia cases, correlation type (Pearson, partial, or biserial), diabetes measure (diabetes diagnosis or glucose marker), MMSE score, and APOEe4 carriership (yes/no). All analyses were performed using the metafor package in R.ResultOur meta‐analysis showed small but significant associations of diabetes measures with increased (more normal) levels of amyloid‐beta42 (r = 0.08, p = 0.04, Figure 1) and increased (more abnormal) levels of p‐tau (r = 0.09, p = 0.04, Figure 2) and t‐tau (r = 0.10, p = 0.04, graph not shown as comparable to p‐tau). Heterogeneity was high for all outcomes (I2>60%, p<0.05 for Q‐test, wide prediction intervals). Meta‐regression analyses showed that heterogeneity in CSF amyloid could partly be explained by setting, as the association between diabetes measures and amyloid was only present in memory clinic studies as compared to population studies (difference estimate = 0.14, p = 0.03). Similarly, studies with more dementia cases showed a stronger association with amyloid (slope estimate = 0.0029, p = 0.001). No other moderating effects were found.ConclusionOur findings suggest that diabetes measures are associated with tau‐related neurodegeneration that is independent from amyloid. This is valuable for improving diagnostics and treatment of patients with diabetes and AD.
Metabolites and Brain Age in a Puerto Rican Cohor
Authors: Gordon Scot , Koo Bang‐Bon , Scott Tammy , Bigornia Sherman J , Bhadelia Rafeeque , Tucker Katherine L , Palacios Natalia 
Published: December 2023

AbstractBackgroundSeveral studies have examined metabolomic profiles in relation to Alzheimer’s disease and related dementia ADRD risk, however, few studies have focused on minorities, such as Latinos or examined MRI‐based outcomes.MethodsThis study examined the association between plasma metabolites and MRI‐derived AD/ADRD markers including brain age deviation and hippocampal volume in the Boston Puerto Rican Health Study (BPRHS). We used multiple linear regression, adjusted for covariates, to examine the association between metabolite concentration at baseline and brain age deviation in the Boston Puerto Rican health Stdy. Metabolites were measured with untargeted metabolomic profiling (Metabolon, Inc) at baseline. Brain age deviation was calculated as chronologic age minus MRI‐estimated brain age, representing the rate of biological brain aging relative to chronologic age. We further examined if metabolites associated with brain age were similarly associated with hippocampal volume.ResultsSeveral metabolites including isobutyrylcarnitine, propionylcarnitine (BCAA metabolism), phenylacetylglutamine, phenylacetylcarnitine (acetylated peptides), p‐cresol‐glucuronide*(tyrosine metabolism), and trimethylamine N‐oxide (TMAO) were inversely associated with brain age deviation. Taurocholate sulfate, a bile salt, was associated with better brain aging.ConclusionsThe metabolites identified in this study are generally consistent with prior literature and highlight a role of branched chain amino acids, TMAO and microbially derived in cognitive decline in cognitive decline.
The cerebrospinal fluid A‐T+ Alzheimer disease biomarker profile: prevalence and clinical relevance
Authors: Eriksson Pontus , Simrén Joel , Brum Wagner Scheeren , Ennis Gilda E. , Kollmorgen Gwendlyn , Carboni Margherita , Langhough Rebecca E , Jonaitis Erin M. , Van Hulle Carol A. , Betthauser Tobey J , Carlsson Cynthia M. , Asthana Sanjay , Ashton Nicholas J. , Johnson Sterling C , Shaw Leslie M. , Blennow Kaj , Andreasson Ulf , Bendlin Barbara B , Zetterberg Henrik 
Published: December 2023

AbstractBackgroundThe cerebrospinal fluid (CSF) amyloid β‐negative and tau‐positive (A‐T+) biomarker profile, as defined by normal amyloid β42/40 ratio (Aβ42/40) and increased phosphorylated tau (p‐tau), is sometimes seen in daily clinical practice. However, knowledge is lacking on its prevalence and whether patients with this profile are at risk for biological disease progression and cognitive decline.MethodIn this study, data from four cohorts were included: UGOT (the clinical laboratory database at Sahlgrenska University Hospital, Gothenburg), Alzheimer’s Disease Neuroimaging Initiative (ADNI; cognitively unimpaired [CU] and mild cognitive impairment [MCI] individuals), Wisconsin Registry for Alzheimer’s Prevention, and Wisconsin ADRC cohorts (latter two analyzed jointly, “WISC”; predominantly CU individuals). Repeated measures of cognitive decline (modified preclinical Alzheimer’s composite [mPACC] in ADNI, and PACC‐3 in the WISC sample), amyloid accumulation (only in ADNI: [18F]‐florbetapir amyloid positron emission tomography [PET]) neurodegeneration (only in ADNI: magnetic resonance imaging [MRI], [18F]‐fluorodeoxyglucose PET [FDG‐PET]), and cross‐sectional tau PET ([F18]‐flortaucipir in ADNI and [F18]‐MK6240 in WISC) were used as exposures.ResultIn the UGOT cohort, a total of 7679 individuals were included (46Conclusions6% women; mean [SD] age, 71.0 [8.3] years). Further, 970 individuals from ADNI (45.8% women, mean [SD] age, 72.8 [7.0]), and n = 519 individuals from WISC (66.7% women, mean [SD] age, 59.7 [7.3]) cohorts were included. The prevalence of the A‐T+ profile in the UGOT cohort was 4.1%, compared with A+T+ that constituted 36%, A‐T‐ 42%, and A+T‐ 17%. In ADNI and UGOT, A‐T+ had higher concentrations of Aβ42 and Aβ40 compared to A‐T‐ individuals. The prognosis of CSF biomarker profiles was determined with linear mixed effects models (ADNI and WISC). The A‐T+ profile, compared with A‐T‐, presented no statistically significant rates of cognitive worsening (ADNI and WISC p>0.05), or in longitudinal changes in Aβ‐PET, FDG‐PET, and hippocampal atrophy (all p>0.05), within the ADNI subsample. Cross‐sectionally, A‐T+ individuals had similar tau‐PET uptake to A‐T‐ individuals (p>0.05).ConclusionThe CSF A‐T+ profile is to be considered clinically benign, as individuals with this profile do not have a higher rate of cognitive decline compared with biomarker‐negative individuals and do not display signs of amyloid accumulation or progressive neurodegeneration.