bluuebunny/crossref_metadata_2025_split huggingface dataset:
Feasibility of longitudinal automated cognitive assessment in the stroke pathway
Authors: Blackburn Daniel J , Bell Simon M , Harkness Kirsty , O'Malley Ronan , Chapman Larissa , Lunn India , Mirheidari Bahman , Christensen Heidi 
Published: December 2023

AbstractBackgroundStroke, post‐stroke dementia and post‐stroke cognitive impairment prevalence is rising significantly, placing an increasing burden on healthcare systems. Standardised pen and paper tools for cognitive assessment require clinical time. There is increasing research into the use of automated cognitive assessment. CognoSpeak (https://cognospeak.github.io/website/) is a fully automated cognitive assessment tool based in language an interaction. A virtual clinician asking questions and listening to responses using automatic speech recognition and Machine Learning algorithms.MethodsPatients who passed the eligibility criteria of having recent acute stroke/TIA, and do not have pre‐existing dementia, severe aphasia, deafness, or too medically unwell were approached to consent to speak to CognoSpeak. Participants completed the CognoSpeak assessment on the ward or at home via a web‐version, as well as MOCA and GAD and PHQ9.ResultsRecruitment started December 2020 and we approached 950 people and recruited 114 participants, with 20 having 6 months follow‐up and 5 12 months follow‐up. The mean age was 61.77 (SD 15.07). Most participants were recruited from Sheffield 71 (68%).The majority had ischemic stroke (67%) & mild stroke according to the NHISS (63%). The most common risk factor was hypertension (19%), and the majority of participants had no symptoms of disability before their stroke (22%). GAD and PHQ9 scores were collected.ConclusionIt is feasible to complete automated cognitive assessment with the stroke population. There remains barriers in utilising technology within this acute and especially longitudinal cognitive assessment in stroke survivors, where rates of anxiety in hospital and at follow‐up appointments may reflect rapid discharge and changes in the stroke pathway during the initial covid pandemic.
Novel small molecules therapeutics for FTD/ALS reduce TDP43 related pathology
Authors: Mathur Vidhu , van Hummel Annika , Sabale Miheer , Ke Yazi D. , Liu Xikun , Bowers Michael T , Burke Kevin , Kokes Marcela , Shao Eric Q , Schwarz Jacon , Planey Katie 
Published: December 2023

AbstractBackgroundTDP43 aggregation and mis‐localization is a hallmark of sporadic Amyotrophic Lateral Sclerosis (ALS) and TDP‐related Frontotemporal dementia (FTD‐TDP). Hyperphosphorylated and ubiquitinated cytosolic TDP43 aggregates have been identified in post‐mortem tissue from disease patients. However, no therapies targeting TDP43 are in the clinic.MethodUsing our novel machine learning platform, we identified compounds that can disaggregate toxic oligomers of amyloid like proteins including TDP43.ResultWe show that a TDP43 peptide can spontaneously form trimers, tetramers, hexamers and octamers in vitro using high resolution ion‐mobility mass spectrometry. Two of our compounds reduce these presumed toxic oligomers and restore physiologically relevant monomers and dimers. Furthermore, our compounds dose‐dependently reduce cytoplasmic aggregates in a cellular TDP43 aggregation model. These compounds show low plasma and brain homogenate binding, high metabolic stability, are orally bioavailable and are highly blood‐brain barrier permeable. Finally, our compounds were tested in a doxycycline‐repressible iTDP43A315T mouse model of ALS. Daily oral dosing of the compounds for approximately two months did not cause any toxicity in the mice at two doses. Both drugs were detectable at high concentrations in the brains of the mice at the end of the experiment. Importantly, drug treatments showed improvement in a motor behavior test and alleviated a disinhibition phenotype in an elevated plus maze test in the diseased mice. Further analysis of target engagement and other downstream efficacy markers is ongoing.ConclusionAll together, these in vitro cell‐based and preliminary in vivo mouse model data show that the Acelot machine learning platform can identify small molecules that have therapeutic potential for ALS, FTD and other amyloid‐associated diseases.
iPSC‐derived cortical neurons of sporadic Alzheimer’s disease patients reflect their clinical vulnerability
Authors: Bertherat Féodora , Ng Bryan , Bengoa‐Vergniory Nora , Carlyle Becky C. , Wade‐Martins Richard 
Published: December 2023

AbstractBackgroundiPSC‐derived cortical neurons from sporadic Alzheimer’s Disease (AD) patients were used to compare cellulare phenotypes in response to AB or tau insults with clinical data of the individual patients.MethodWe generated14 iPSC lines from sAD patients from the Deep and Frequent Phenotyping study, which has collected a battery of clinical data from early‐stage sAD patients. Phenotypes such as neurite loss, axonal branching or cytotoxicity were measured in iPSC‐derived cortical neurons following Amyloid Beta oligomer treatment.ResultIndividual AD patient lines exhibit significantly different levels of neurite loss and decreased axonal branching due to Amyloid Beta. This differences is significantly correlated with clinical vulnerability of the individual patients.ConclusionDifferences in disease vulnerability in patients observed in clinic is reflected in patient iPSC lines when treated with Amyloid Beta.
Efficacy of the murine version of E2814 in a validated AD brain seed‐injection model in hTau mice
Authors: Talma Sonia , Gartlon Jane , Takahashi Eri , Horie Kanta , Wildsmith Kristin R , Staddon James , De Silva Rohan , Roberts Malcolm 
Published: December 2023

AbstractBackgroundAs Alzheimer’s disease progresses, pathological tau spreads through the brain via synaptically connected pathways. Tau proteins containing the microtubule binding region (MTBR) may be essential to form extracellular ‘seeds’ that initiate and propagate pathology. To simulate this process preclinically, we have further characterised an AD brain‐derived seed‐injection in vivo model using hTau mice that overexpress all six isoforms of human wild‐type tau (Andorfer et al., 2003). In further follow up studies, mice were treated with the 7G6‐IgG2a antibody, which is the murine counterpart of E2814, an anti‐tau antibody currently in clinical trials that recognises the MTBR (Roberts et al., 2020).MethodIn a validation study, insoluble fraction or whole homogenate from human AD brain (‘seed’) was directly injected into the left hippocampus of 6‐month‐old hTau mice or their tau null littermates. At different times after seed injection, the generation of insoluble tau was quantified in selected brain regions (hippocampus and cortex) by western blotting following tissue fractionation with detergents.In a subsequent therapeutic intervention study, animals were treated peripherally with a control mouse IgG2a antibody or 7G6‐IgG2a at different doses (3, 10, and 40 mg/kg). Levels of insoluble tau in the hippocampus and cortex were quantified as described above. Terminal CSF was also collected to measure target engagement of antibody. Additionally, immunohistochemistry using the AT8 antibody that detects pathological forms of phospho‐tau proteins was performed on brains from a limited number of animals receiving the highest dose of control IgG2a or 7G6‐IgG2a.ResultAD brain insoluble fraction was superior to homogenate when used as a seed in the hTau mouse.Peripheral treatment of seeded hTau mice with the 7G6‐IgG2a antibody (40 mg/kg) resulted in a significant reduction of insoluble tau in multiple brain regions. Antibody target engagement also increased in the CSF from treated animals in a dose‐dependent manner.ConclusionAD seed‐injection in hTau mice has been further validated and can be used in therapeutic intervention studies. The murine version of E2814, 7G6‐IgG2a, reduced pathological tau seeding and spreading in this model. The nonclinical data obtained here further supports E2814 being tested in clinical trials.
Small RNAs, short but mighty: the unknown players in AD pathobiology
Authors: Beric Aleksandra , Baldrich Patricia , Cruchaga Carlos , Ibanez Laura 
Published: December 2023

AbstractBackgroundMicroRNAs (miRNAs) are known to be involved in Alzheimer’s disease (AD), but little is known about the other classes of small RNAs (sRNAs). We performed the first high throughput, unbiased study of sRNAs in AD brains aiming to build regulatory networks involved in AD pathogenesis.MethodSampling included 244 parietal brain samples from the Knight‐ADRC, 93% of which were AD cases, 90% male, and with a mean age of 83. After RNA extraction with a Maxwell RSC instrument, we generated sRNA libraries using the RealSeq®‐AC sRNA kit version 2. Libraries were aligned to the reference genome and known small RNAs using Bowtie2. After stringent quality control we performed differential expression analyses using DESeq2, adjusting by age, sex, post‐mortem interval and methodological variables. Finally, we integrated the sRNA data with RNA‐seq data from the same samples to identify correlations with known AD genes.ResultWe identified four miRNAs and fifty‐six Piwi‐interacting RNAs (piRNAs) and one snoRNA that are significantly dysregulated in AD brains. We observed no significantly dysregulated tRNAs, suggesting that translational machinery was intact. We found significant positive correlation between miR‐6126 and miR‐3614‐3p, miR‐6126 and two piRNAs, as well as relationships among several piRNAs. Further, we identified dysregulated sRNAs that significantly correlate with AD genes such as APP, PSEN1, and PSEN2. For example, piR‐3746502 negatively correlates to over ten AD‐genes but associates with MS4A4A and TREM2 in the opposite direction of other AD genes, consistent with biological knowledge.ConclusionOur findings emphasize the importance of non‐coding RNAs in the pathobiology of AD. We showed that sRNAs beyond miRNAs contribute to AD and that large‐scale studies of sRNAs in brain are crucial to understand the regulation of the pathways involved in AD pathogenesis. Here, we described that several sRNAs involved in the regulation of known AD genes, with associations in the expected direction.
Assessment of RMTs for Discriminating Stages of Alzheimer’s Disease
Authors: Lentzen Manuel , Vairavan Srinivasan , Curcic Jelena , Atreya Alankar , Hinds Chris , Muurling Marijn , Conde Pauline , Grammatikopoulou Margarita , Lazarou Ioulietta , Nikolopoulos Spiros , Coello Neva , de Boer Casper , Aarsland Dag , Brem Anna‐Katharine , Fröhlich Holger ,   RADAR‐AD
Published: December 2023

AbstractBackgroundRADAR‐AD is a European project in the context of the Innovative Medicine Initiative (IMI) focusing on the earlier identification of patients at risk for developing Alzheimer’s Disease (AD) via a panel of remote monitoring technologies (RMTs), including smartphone apps and wearable devices.MethodWe examined the ability of 6 RMTs (Altoida, Axivity, Banking app, Fitbit, Physilog, and Mezurio) to distinguish between healthy controls (HC) and disease stages of preclinical (PreAD), prodromal (ProAD), and mild to moderate Alzheimer’s disease (MildAD) based on 175 patients (interim analysis). We trained three machine learning classifiers (Logistic Regression, Random Forest, and XGBoost) in a pairwise setting (HC vs. PreAD, HC vs. ProAD, HC vs. MildAD, PreAD vs. ProAD, and ProAD vs. MildAD). Since the interim dataset is still limited, we performed repeated, stratified nested cross‐validation to get a robust performance estimate. Each classifier was trained with the features of the different devices and a set of baseline variables. The latter include a patient’s gender, age, years of education, and body mass index (BMI) when physical conditions might play a role (Axivitiy, Fitbit, Physilog). In addition, we checked whether specific patterns of the study groups allowed discrimination of the different study groups based on the baseline variables alone. Therefore, we trained one Logistic Regression model with these variables and compared the performance of the other three models with this baseline. The models trained with the baseline and questionnaire‐based data served as the reference value in our benchmark that represents how well the discrimination of the different groups works with clinical tests.ResultOur preliminary data show that RMTs can identify patients already in a prodromal disease stage (AUC ∼69%, Figure 1). Furthermore, the pairwise combination of data from a banking app and an app monitoring functional cognitive abilities via an augmented reality game slightly increased our model’s discriminative ability (Altoida ‐ Banking, Figure 2). The overall best performance was achieved when combining RMTs with the Amsterdam I‐ADL questionnaire.ConclusionOur results demonstrate the potential of RMTs and the Amsterdam I‐ADL questionnaire for identifying patients in prodromal stage in primary care settings.
Implementation of a 3‐Dimensional Embodied Conversational Agent to Support Neurologists in Conducting Cognitive Assessment in Alzheimer Patients
Authors: Sherimon Vinu , Sherimon P.C. , Nair Rahul V. 
Published: December 2023

AbstractBackgroundAlzheimer’s disease is a universal medical and public health challenge. A timely identification of this ailment can enhance both the standard of care and the patient’s quality of life. Alzheimer’s diagnosis includes a critical component called cognitive assessment. These examinations have been carried out by neurologists, manually and digitally since the development of clinical neurological tests. But it’s obvious that integrating AI technologies into such assessments has many advantages. This research paper describes the implementation of a 3‐Dimensional Embodied Conversational Agent to support Neurologists in conducting cognitive assessments in Alzheimer patients.MethodTwenty‐two questions are included in the assessment. The assessment checks different mental abilities of patients such as time orientation, place orientation, ability to recall things, concentration skills, language skills, ability to follow written and oral instructions, visual interpretation skills, etc. A score is given for each correct answer. A normal score must be higher than 24. A score of 24 or less is typically seen as abnormal and indicative of possible cognitive impairment further subject to detailed analysis of a neurologist as the result may occasionally be impacted by certain physical impairments, language or speech barriers, education level, or cultural differences.The 3D agent was created using software such as Blender, iclone7, Adobe Photoshop, JavaScript, and MIT App Inventor. Text‐to‐speech synthesis algorithms were used to convert the questions to speech. The answers given by the user will be recognized using Natural Language Processing (NLP) algorithms. Correspondingly, a score will be awarded. TinyDB is used for local storage and CloudDB for web storage.ResultThe 3D agent receives the speech input, analyzes the input, and provides a vocal response. As per the total score, it will suggest suitable recommendations vocally. Also, an assessment report with the AI impression is generated.ConclusionThe implementation of a 3‐D Embodied Conversational Agent to support Neurologists in conducting cognitive assessment is portrayed in this research. Instead of trying to replace clinicians, Artificial Intelligence aims to help them and make their tasks simpler.
Design, Synthesis and Evaluation of substituted Chromones as Acetylcholinesterase Inhibitors for the Treatment of Alzheimer’s Disease.
Authors: Kumar Naveen , Kumar Vijay , Kumar Vinay , Kailash  , Kumar Vinod 
Published: December 2023

AbstractBackgroundAcetylcholinesterase (AChE) is one of the frontline targets involved in the progression of Alzheimer’s disease. AChE inhibitors are prescribed as the few drug therapies that have been proven clinically useful in the treatment of Alzheimer’s disease[1, 2]. AChE is involved in the termination of impulse transmission by rapid hydrolysis of the neurotransmitter acetylcholine in numerous cholinergic pathways[3]. The enzyme inactivation induced by various inhibitors, leads to acetylcholine accumulation, hyperstimulation of nicotine and muscarinic receptor and disrupted neurotransmission.MethodA series of chromone derivatives were virtually screened, synthesised and biologically evaluated as acetylcholinesterase inhibitors. All the compounds were characterised by 1H‐NMR, 13C‐NMR and mass spectrometry.ResultThe in‐vitro evaluation of the compounds against hAChE enzyme showed promising inhibition varying in lower micromolar range. In the synthesized series, NSS‐17 is found to be the most potent AChE inhibitors (IC50 = 1.59± 0.02 μM). In molecular docking studies, compound NSS‐17 showed similar interaction to AChE (1EVE) as shown by reference compound donepezil.ConclusionThus, NSS‐17 can be used as promising lead for the development of more potent AChE inhibitors by further biological assays and in‐vivo studies.
References
[1] B. Kumar, A.R. Dwivedi, B. Sarkar, S.K. Gupta, S. Krishnamurthy, A.K. Mantha, J. Parkash, V. Kumar, 4,6‐Diphenylpyrimidine Derivatives as Dual Inhibitors of Monoamine Oxidase and Acetylcholinesterase for the Treatment of Alzheimer’s Disease, ACS Chemical Neuroscience 10(1) (2019) 252‐265.[2] B. Kumar, V. Kumar, V. Prashar, S. Saini, A.R. Dwivedi, B. Bajaj, D. Mehta, J. Parkash, V. Kumar, Dipropargyl substituted diphenylpyrimidines as dual inhibitors of monoamine oxidase and acetylcholinesterase, European Journal of Medicinal Chemistry 177 (2019) 221‐234.[3] B. Kumar, Sheetal, A.K. Mantha, V. Kumar, Recent developments on the structure–activity relationship studies of MAO inhibitors and their role in different neurological disorders, RSC Advances 6(48) (2016) 42660‐42683.
Amyloid‐β Pathology Exacerbates Aging‐Induced Dysregulation of C1q Expression in Cortical Neurons
Authors: Semmedi Cemaliye , Moore Maxwell B , Mostany Ricardo 
Published: December 2023

AbstractBackgroundAging, even in the absence of age‐related pathologies such as Alzheimer’s disease (AD), is associated with a loss of neuronal function and structure, and cognitive decline. An initiator of the classical complement cascade, C1q, which enhances the immune response in the periphery, has been shown to mediate synaptic pruning in the developing brain (Stevens et al., 2007). It has been hypothesized that this cascade may be implicated in the cognitive decline associated with aging, as well as neurodegenerative diseases, such as AD.MethodIn this study, magnetic‐activated cell sorting (MACS), a cell separation technology based on the use of antibody‐conjugated beads, was utilized to isolate neurons from the whole cortex tissue dissociations of wild‐type (Thy1‐GFP) and AD model (APPNL‐G‐F‐GFP) mice at different life stages: 3 months (young adult), 6 months (adult), 12 months (middle‐aged adult), and > 21 months of age (aged). Droplet‐digital polymerase chain reaction (ddPCR), an advanced PCR technology with higher accuracy and consistency than traditional PCR methods, and Simple Western, an automated western blot system, were utilized to quantify the expression of C1QA and C1q, respectively, in isolated cortical neurons.ResultThere is a significant aging‐induced increase in C1q levels in cortical neurons of both wild‐type and AD model aged mice. Interestingly, in middle‐aged AD mice, in which the deposition of amyloid‐β plaques is already severe, the levels of C1q are significantly elevated compared with wild‐type mice, and the expression levels are comparable to that of aged mice of both genotypes.ConclusionThese findings support the notion that the initiation of the classical complement cascade by cortical neurons is upregulated with healthy aging, and this aging‐induced upregulation is accelerated by amyloid‐β pathology.
The clinical usefulness of plasma biomarkers of neuronal dysfunction in Alzheimer’s disease
Authors: Mroczko Barbara , Kulczynska‐Przybik Agnieszka , Blennow Kaj , Dulewicz Maciej , Ashton Nicholas J. , Karikari Thomas K , Mroczko Jan , Borawska Renata , Slowik Agnieszka , Zetterberg Henrik 
Published: December 2023

AbstractBackgroundAlzheimer’s disease (AD) is one of the most common neurodegenerative disorders, and one of the most significant medical and social problems worldwide. Neurodegeneration, which is a pivotal mechanism underlying the disease, begins a few decades before the first symptoms appear. Therefore, establishing biomarkers that allow for the detection of this process as early as possible is vital. Mounting evidence indicates the crucial role of GFAP and NFL in the pathology of neurodegeneration in AD. The aim of the present study was to assess plasma concentrations of GFAP and NFL, and to test their potential utility in AD diagnosis.MethodPlasma concentrations of GFAP and NFL were measured using a Single molecule array (Simoa), while the classical biomarkers (Aβ‐42, Aβ‐42/Aβ‐40, tau, and pTau181) were assessed in the cerebrospinal fluid (CSF) of 20 AD patients and 18 elderly subjects without cognitive deficits using ELISA technique.ResultPlasma concentrations of GFAP and NFL were significantly higher in AD patients as compared to non‐demented controls. The levels of plasma GFAP correlated negatively with MMSE, and CSF Aβ‐42, and positively with plasma concentrations of NFL, and CSF tau proteins in the whole study group. Furthermore, in the AD group, the association between GFAP and NFL was revealed.ConclusionPresented findings indicate that plasma GFAP and NFL could be applied as a non‐invasive and accessible tool for detection of early neuronal dysfunction in patients with AD.