bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genome‐wide CRISPR knockout screening to identify key regulators of phagocytosis in induced pluripotent stem cell derived microglia
Authors: Washer Sam J , Perez‐Alcantara Marta , Navarro‐Guerrero Elena , Steer Juliette , Chen Yixi , McWilliam Joe , Cowley Sally A , Ebner Daniel , Bassett Andrew R 
Published: December 2023

AbstractBackgroundA whole genome knockout CRISPR screen in human induced pluripotent stem cell (hiPSC) derived microglia was undertaken to identify regulators of phagocytosis. The secondary objective was to cross reference these genes to Alzheimer’s Disease genome‐wide association studies to provide potential therapeutic targets for drug development.MethodHiPSC‐derived microglia precursor cells were transduced with the TKOv3 genome‐wide CRISPR/Cas9 knockout library and differentiated for two weeks to microglia in our recently published media. hiPSC‐microglia were then fed dead GFP/mCherry fluorescent labelled SH‐SY5Y neuronal cells as phagocytic meal. Phagocytosis proceeded for 6 hours before washing away non‐phagocytosed SH‐SY5Y, harvesting and fixing the hiPSC‐microglia. hiPSC‐microglia were sorted into high and low levels of phagocytosis by fluorescent activated cell sorting (FACS) for single mCherry‐positive cells as GFP is quenched due to a low pH environment. Genomic DNA was extracted from sorted cell populations and the integrated guide RNA were sequenced by Illumina Novoseq.ResultMicroglia were successfully transduced at a multiplicity of infection at 0.7 to maximize single guide integration. Successful phagocytosis was observed via FACS, with over 60% of hiPSC‐microglia phagocytosing dead neurons after 6 hours. Four populations of varying levels of phagocytosis were harvested and genomic DNA extracted and sequenced.ConclusionWe have developed a pipeline for the first successful genome‐wide CRISPR knockout screening in hiPSC‐microglia and have used this to identify regulators of phagocytosis.
The association between air pollution and dementia: results from the Cognitive Function and Ageing Study II and Wales
Authors: Wu Yu‐Tzu , Prina Matthew , Zied Eman , Matthews Fiona E 
Published: December 2023

AbstractBackgroundAir pollution has been recognised as one of the key modifiable risk factors for dementia. In the UK, there is a lack of evidence from population‐based cohort studies including older people from different backgrounds and living environments. Using two multicentre ageing cohorts in England and Wales, the aim of this study is to investigate the potential impact of air pollution on dementia in later life.MethodThis study was based on the Cognitive Function and Ageing Study (CFAS) II (2008‐2011) and Wales (2011‐2013), two longitudinal studies of people aged 65 or above across five centres in England (Cambridgeshire, Newcastle upon Tyne, Nottingham) and Wales (Gwynedd, Neath Port Talbot). A two‐year follow‐up wave was carried out for both studies. Dementia was identified using the Geriatric Mental State and its diagnostic algorithm, Automated Geriatric Examination for Computer Assisted Taxonomy (GMS‐AGEACT). Based on the participants’ postcodes at the baseline, exposure to four air pollutants in 2012, including nitrogen dioxide (NO2), ozone (O3), particulate matter with a diameter ≤10 microns (PM10) and ≤2.5 microns (PM2.5), was estimated using the Community Multiscale Air Quality pollution modelling at a resolution of 20×20 m. Multistate modelling was used to investigate the effects of air pollution exposure on risk of developing dementia over the follow‐up period, incorporating mortality (from national death certification) and adjusting for age, sex, education, study centre and area deprivation.ResultAmong the 11329 participants in CFAS II (N = 7753) and Wales (N = 3576), the median exposure was 17.7 (IQR = 11.6) µg/m3 for NO2, 43.8 (IQR = 11.1) µg/m3 for O3, 15.5 (IQR = 3.1) µg/m3 for PM10 and 10.1 (IQR = 2.8) µg/m3 for PM2.5 and large variation was observed across the five centres. Per unit increase in NO2 exposure was associated with a higher risk of dementia in CFAS II (HR: 1.07; 95%CI: 1.03, 1.12) but not the Welsh cohort (HR: 0.93; 95%CI: 0.86, 1.00) after adjustment. For the other air pollutants, the associations were unclear.ConclusionOur study suggests limited evidence for the impacts of air pollution on dementia. Other environmental factors may influence individual exposure to air pollution and altogether have a complex effect on cognitive health in later life.
Challenges of Dementia care in times of COVID. Change and survive or Perish
Authors: Kremer leonardo Janus 
Published: December 2023

AbstractBackgroundThe COVID era forced dementia centers to reshaped their strategies in order to keep providing care to patients and to their familiesMethodAdaptation of simple social media tools as a telemedicine systemResultVery usefulConclusionOur Institute faced the same challenges that all other institutions, having to deal with isolation, fear, decreased income and uncertainty. Patients and caregivers suffered enormously these facts.We developed a complex system of telemedicine in order to keep being responsible for the continuing care. Our country was not adapted in technology by that time and most the families belonged to low income sector. Most of them (65% approximately) did not have even a personal computer at home.We adapted neuropsychiatric consultations, neuropsychological evaluations and cognitive training using simple tools such as Instagram, Zoom, Meet and mainly Whatsapp.We were able not only to provide the very same standard of care to patients but also the hold the needs of the caregivers.This rudimentary structure created during the sanitary emergency was the basis for a larger, more complex and sophisticated web platform that we developed and today we are using as a virtual Alzheimer Institute, being able to reach patients and caregivers worldwide.
Healthy Dietary Intake Reduces Longitudinal Brain Iron Accumulation in Older Adults
Authors: Zachariou Valentinos , Bauer Christopher E. , Seago Elayna R. , Gold Brian T. 
Published: December 2023

AbstractBackgroundBrain iron, which tends to accumulate with normal aging, negatively affects cognitive performance. However, the impact of brain iron on cognition appears modifiable. In a recent study from our group [1], we demonstrated that those older adults with high dietary intake of antioxidants, iron chelating nutrients and polyunsaturated fatty acids (Factor 2 in [1]), tended to have lower brain iron and better working memory performance than expected for their age. Here, we extend our previous work by evaluating associations between baseline consumption of Factor 2 nutrients and longitudinal brain iron accumulation, evaluated three years after baseline.MethodsForty‐three, cognitively normal, older adults (26 women, age range 63‐88 years) underwent MRI‐based structural brain imaging and quantitative susceptibility mapping for assessment of brain iron concentration at two time points: baseline (T1) and three years after baseline (T2). Additionally, at T1, nutritional‐intake was assessed via a validated questionnaire. Nutrients were grouped into nutrition factors based on previous literature and factor analysis. Factor 2, comprised vitamin E, lysine, DHA omega‐3 and LA omega‐6, representing antioxidants, iron chelating nutrients and polyunsaturated fatty acids.ResultsVoxelwise, whole‐brain, linear mixed‐effects models (qFDR < 0.05), controlling for longitudinal gray matter volume alterations, age, gender and education, revealed brain iron accumulation within several subcortical and cortical brain regions. Importantly, a significant time point by nutrition interaction was also observed. Specifically, those participants who consumed higher amounts of Factor 2 nutrients at baseline exhibited lower longitudinal brain iron accumulation within the left middle frontal gyrus, left superior parietal lobule, left insular cortex, right inferior temporal cortex, and bilateral hippocampus. Time point by nutrition interactions were not observed for other nutrition factors discussed in [1], such as those comprised of nutrients found in fruits and vegetables, or in green tea.ConclusionOur results indicate that dietary patterns rich in oxidative stress‐reducing antioxidants, iron chelating nutrients and polyunsaturated fatty acids may slow down age‐related, brain iron accumulation in older adults.References:[1] V. Zachariou et al., “Healthy dietary intake moderates the effects of age on brain iron concentration and working memory performance,” Neurobiol Aging, vol. 106, pp. 183‐196, Oct. 2021
A Clinical Cognitive Resilience Score Based on Residual Approach in Alzheimer’s Disease Continuum
Authors: Ersoezlue Ersin , Rauchmann Boris‐Stephan , Perneczky Robert ,   Alzheimer’s Disease Imaging Initiative (ADNI)
Published: December 2023

AbstractBackgroundHighly varying cognitive abilities among individuals facing pathological alterations, e.g. in Alzheimer’s disease (AD), is conceptualized by the cognitive reserve (CR) hypothesis[1]. The growing interest in prevention and intervention methods brings many new challenges for precision medicine[2]. Hereby, studies on the residual approach for estimating CR, i.e. cognitive resilience, are emerging[1], while the employed methods are highly variable among studies. We aim to develop a standardized and simplified clinical score that predicts CR individually.MethodCognitively normal (CN) and β‐amyloid(Aβ)‐negative n = 86 participants and n = 707 individuals with Aβ+ from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort ‐ADNI‐1/GO and 2‐ were included in the study. The Aβ+ group was stratified as CN+, mild cognitive impairment (MCI+) and AD dementia (ADD+) subgroups. A residual factor score (CR‐Factor) using principal component analyses was derived, including cognitive composite scores and continuous CSF‐Aβ and CSF‐phosphorylated‐tau. We predicted a CR‐Score through multinomial regression analysis on CR‐Factor, including the modified‐Preclinical‐Alzheimer‐Cognitive‐Composite score and CSF‐Aβ and CSF‐phosphorylated‐tau categories (normal, intermediate range ‐10% borderline towards abnormal values‐ and abnormal) as predictors (Figure‐1). The associations of the CR‐Score with baseline characteristics and longitudinal change in cognition were tested.ResultMultinomial regressions revealed that CR‐Score was positively associated with higher years of education in the entire cohort and subgroups, except ADD+. Moreover, higher CR‐Score was associated with younger age and female sex in CN+, younger age in MCI+ and inversely with Afro‐American race in the entire cohort (Table‐1). In linear mixed models, higher CR‐Scores predicted a slower increase of Clinical Dementia Rating‐sum of boxes in MCI+ and ADD+ and of AD‐Assessment‐Scale cognitive‐subscale‐13 in MCI+ (Figure‐2).ConclusionThe framework to derive a formula that operationalizes CR on an individual level might provide a simplified and yet effective method for clinical studies with patients in AD‐continuum, especially prodromal AD, where intervention is emphasized as appropriate[3]. Furthermore, a standardized marker among studies can promote the replicability and comparison of studies on residual methods.[1] Stern Y et al. Alzheimers Dement 2020;16:1305‐11.[2] Livingston G et al. Lancet 2020;396:413‐46.[3] Cummings J & Fox N. J Prev Alzheimers Dis 2017;4:109‐15.
Precision of clinical diagnosis in neurodegenerative diseases: an investigation of 455 autopsied cases
Authors: Vöglein Jonathan , Kostova Irena , Arzberger Thomas , Herms Jochen , Roeber Sigrun , Danek Adrian , Höglinger Günter , Giese Armin , Levin Johannes 
Published: December 2023

AbstractBackgroundAccuracy of clinical diagnosis in neurodegenerative diseases is critically important for patient care and study recruitment. We aimed to investigate the precision of clinical diagnosis of various neurodegenerative conditions using neuropathological diagnosis for reference.MethodAll 1310 autopsy cases between 1993 and 2017 from the Neurobiobank München (Munich, Germany) were screened for neurodegenerative diagnoses. Neuropathological diagnoses that occurred in at least five cases were included in the study. Real world clinical diagnoses were extracted from medical records of admitting hospitals in Germany and correlated with neuropathological diagnoses. Sensitivity, specificity and accuracy (using receiver operating characteristic (ROC) curves and area under the curve (AUC) analysis) of clinical diagnoses were calculated.ResultThe study included 455 cases with neuropathologically diagnosed Alzheimer’s disease (AD, n = 132), argyrophilic grain disease (AGD, n = 6), corticobasal degeneration (CBD, n = 20), frontotemporal lobar degeneration (FTLD, n = 47), Huntington’s disease (HD, n = 22), Lewy body disease (LBD, n = 104), motor neuron disease (MND, n = 10), multiple system atrophy (MSA, n = 37) and progressive supranuclear palsy (PSP, n = 77). Clinical diagnoses in these cases comprised AD (n = 136), CBD (n = 17), Creutzfeldt‐Jakob disease (CJD, n = 6), dementia with Lewy bodies (DLB, n = 11), frontotemporal dementia (FTD, n = 44), HD (n = 23), MND (n = 20), MSA (n = 36), Parkinson’s disease (PD, n = 92), PSP (n = 60) and vascular dementia (VD, n = 10). Figure 1 illustrates the relationship between clinical (left) and neuropathological diagnoses (right). Figure 2 shows sensitivity, specificity, ROC curves, AUCs including standard errors (SE) and 95% confidence intervals (CI) and p‐values for testing the null hypothesis AUC = 0.5 for clinical diagnoses.ConclusionClinical diagnoses of neurodegenerative diseases exhibited a wide span of sensitivity depending on the particular disease (0‐100%) while specificity was high for all clinical diagnoses (89.5‐100%). Accuracy of clinical diagnoses as determined with AUC analysis was very good (AUC>0.9) for HD, MND and MSA, good (AUC = 0.8‐0.9) for AD, DLB/PD and PSP, moderate (AUC = 0.7‐0.8) for FTD, poor (AUC = 0.51‐0.7) for CBD and bad/no discrimination capacity (AUC = 0.5) for AGD. Based on these findings, an increase of sensitivity of clinical diagnoses may be key to improve correct identification of neurodegenerative diseases. This may be possible through development and clinical implementation of molecular biomarkers that are able to indicate the causal proteinopathies of neurodegenerative diseases.
Living without a diagnosis: Quality of life differences between those who screen positive and negative for dementia in rural Kenya
Authors: Farina Nicolas , Musyimi Christine W. , Muyela Levi A. , Masila Joe , Mutunga Elizabeth Kasimu , Ndetei David 
Published: December 2023

AbstractBackgroundWithin Kenya, dementia is commonly under‐recognised and under‐diagnosed. As a result, many people living with dementia do so without any formal support. The DEM‐SKY project seeks to address this gap by implementing a dementia screening program in Kenya using Community Health Volunteers. The aim of this study is to understand some of the consequences of living with cognitive and functional impairment.MethodsOlder adults (aged 60 years and older) were opportunistically screened for dementia using the Brief Community Screening Instrument for Dementia (CSID) within Makueni County, Kenya. Secondary outcomes included Quality of life (EUROHIS‐8) and loneliness (UCLA). Regression models were created to understand how quality of life and loneliness outcomes differ between those who screen positive and negative for dementia.ResultsOf the 672 older adults screened, 31.1% (n = 209) screened positive for dementia. People who screen positive for dementia reported to have poorer quality of life (p = 0.01) and were also lonelier (p = 0.03) than those who screened negative. Quality of life (b = ‐0.93, 95%CIs = ‐1.83 to ‐0.02; p = 0.04) and loneliness (b = 0.34, 95%CIs = 0.03 to 0.65; p = 0.03) outcomes remained statistically significant after controlling for age, sex, ethnicity, geographic location, and social status.ConclusionThe findings indicate that people who experience cognitive and functional impairment (indicative of dementia) in Kenya are more likely to be lonely and have poorer quality of life. Further research is needed to understand the underlying mechanisms within a Kenyan context, but our findings are indicative that even without a diagnosis the impact of dementia can be felt by people living with it.
Genome‐wide analysis identifies APOE4 as a strong mitophagy modifier in Lewy body disease
Authors: Hou Xu , Heckman Michael G. , Fiesel Fabienne C , Tiemann Savannah J , Koga Shunsuke , Beasley Alexandra I. , Watzlawik Jens O , Zhao Jing , Johnson Patrick W. , White Launia J , Quicksall Zachary , Zhao Na , Bu Guojun , Dickson Dennis W. , Ross Owen A. , Springer Wolfdieter 
Published: December 2023

AbstractBackgroundLoss of function mutations in PINK1 and PRKN are the most common causes of early‐onset Parkinson disease (PD). The encoded ubiquitin (Ub) kinase PINK1 and the E3 Ub ligase PRKN together regulate the autophagic degradation of dysfunctional mitochondria, termed mitophagy. During this cytoprotective process, PINK1 and PRKN identify and jointly decorate damaged mitochondria with phosphorylated Ub (pS65‐Ub) that serves as the mitophagy tag. Accumulating evidence suggest a pathogenic role for impaired mitophagy in PD and related neurodegenerative conditions. This is in line with our previous finding of increased levels of the mitophagy marker pS65‐Ub in the hippocampus of postmortem Lewy body disease (LBD) brain.MethodWe performed a genome‐wide association study (GWAS) of hippocampal pS65‐Ub level to identify novel regulators of the PINK1‐PRKN‐directed mitophagy in LBD. In our two‐stage GWAS, we obtained 1,012 autopsy confirmed LBD samples (754 discovery stage, 258, replication stage) from Caucasian participants of European ancestry. Using an established, mostly automated workflow, hippocampal sections were immunostained for pS65‐Ub, scanned, and quantified with unbiased algorithms.ResultOur findings identified that APOE rs429358 (β: 0.50, 95% CI: 0.41 to 0.69, p = 8.67×10−25) was very strongly associated with pS65‐Ub levels in LBD brain. The APOE4 genotype is known to exacerbate Aβ and tau deposition. We did observe strong correlations of pS65‐Ub levels with both tau tangle and senile plaque density in the entire LBD cohort. Nevertheless, the increased pS65‐Ub levels in APOE4‐carrying LBD brains were also independent of Aβ and tau deposition in a subgroup (N = 175) with medium levels of these pathologies. To further explore APOE4 effects on mitophagy outside disease context, this observation was also confirmed in APOE‐targeted replacement mice and in induced pluripotent stem cell‐derived astrocytes.ConclusionOur findings nominate a novel mitophagy regulator in LBD brain and highlight a strong association of APOE4 with mitophagy alteration. Our results suggested that APOE4 may mediate mitophagy defects through two mechanisms, by aggravating Alzheimer’s‐type pathologies and also independent of them. With APOE4 being the strongest known risk factor for Alzheimer’s disease and dementia with Lewy bodies, our findings suggest a common mechanistic link underscoring the importance of mitochondrial quality control.
The NeuGRID Workflow: a “Swiss Army knife” for MRI processing
Authors: De Francesco Silvia , Archetti Damiano , Redolfi Alberto 
Published: December 2023

AbstractBackgroundThe advent of big data and artificial intelligence has energized the neuroimaging community with powerful processing tools and the need for large‐scale computational resources for data analysis has increased. Not all neuroscientists have access to extensive resources or have sufficient expertise to configure these libraries, making them difficult to use.MethodA collection of popular MRI scan processing software, (i.e.: Fsl, FreeSurfer, Ants, SPM, Adaboost, Neuromorphometrics, LPA, Tracula) was selected as a proof of concept to be included in the NeuGRID Workflow to produce an advanced tool for group analysis and biomarkers assessment.ResultThe NeuGRID Workflow was designed to allow the user to build a custom MRI processing pipeline by means of a layered structure (Fig.1) available for users at the URL https://neugrid2.eu/index.php/workflowgroup. In the first layer, the user must upload a compressed file containing T13D, FLAIR, and DWI scans of subjects. In the second layer, the user selects which kind of MRI sequence to process. If DICOMs were uploaded, the third layer provides tools to convert DICOMs into NIFTI, the default format for all subsequent workflow processes. All DICOMs are anonymized upon upload. The fourth layer allows the user to choose how images are preprocessed, and the preprocessing pipelines can be customized for different modalities. In the final layer, the user can choose how to analyze the images to calculate volume, thickness, area and curvature of brain regions, quantify white‐matter lesions and reconstruct major white‐matter pathways. The triggered job is efficiently parallelized using a Sun Grid Engine scheduler to reduce computation time. After the scans are processed in the NeuGRID cluster (450 CPUs, 2.5TB memory, 400TB storage), the user is notified by email that the job is finished and the results can be downloaded.ConclusionThe NeuGRID Workflow is a practical tool that allows researchers without computational resources and/or expertise to design a custom pipeline to process large amounts of data from anywhere using a traditional laptop or personal computer. The collection of heterogeneous tools provides a high degree of freedom in pipeline design, making NeuGRID Workflow a Swiss Army knife for MRI processing
Characterization of Novel Antioxidant VANL‐100 on Akt and GSK3B Protein Activity and Expression
Authors: Pfeifer Julia Anne , Saleh Tarek M , Kalisch Bettina E 
Published: December 2023

AbstractBackgroundStrong evidence suggests antioxidant therapies modulate Akt and glycogen synthase 3 beta (GSK3B) signalling pathways–molecular mechanisms tightly correlated with the pathophysiology of Alzheimer’s disease (AD).
MethodThe effects of VANL‐100, a novel antioxidant co‐drug, were characterized on Akt and GSK3B signalling in the SH‐SY5Y human neuroblastoma cell line. Cells were treated with varying doses of VANL‐100 and the effects compared to its parent compounds, naringenin (NGN) and alpha‐lipoic acid (ALA) alone or in combination without a chemical link. After 24 hours of treatment, activation and total protein levels of Akt and GSK3B were assessed by Western blot analysis.
ResultVANL‐100 was 100‐fold more potent at increasing the phosphorylation of Akt (Ser473) (p<0.05) than its parent compounds alone or in combination without being conjugated to one another. Furthermore, VANL‐100 was more effective at inhibiting the activity of GSK3B (Ser9) than either of the parent compounds alone or in combination at a dose of 50uM (p<.05), 100uM (p<.01) and 200uM (p<.05).
ConclusionThese findings suggest that the novel co‐drug VANL‐100 is more effective at modulating Akt and GSK3B activity than its parent compounds, even when they are administered in combination but not chemically‐linked. Since disruptions in Akt and GSK3B signalling pathways are linked to AD, elucidation of compounds such as VANL‐100 that modulate these pathways supports the use of antioxidant conjugates as potential novel therapeutic strategies.