bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Role of Alzheimer’s disease relevant Tau modifications in Neurodegeneration and Mitochondrial dysfunction
Authors: Guha Sanjib K , Nehrke Keith , Johnson Gail VW 
Published: December 2022

AbstractBackgroundAlzheimer’s disease (AD) is a progressive neurodegenerative disorder whose pathological hallmarks include intraneuronal neurofibrillary tangles (NFTs) composed of the microtubule‐associated protein Tau. Tau isolated from AD brain exhibits abnormally high levels of post‐translational modifications (PTMs) including phosphorylation and acetylation at specific epitopes that increase with disease severity and age. In addition, mitochondrial dysfunction is an early feature of AD, and abnormal, toxic tau PTMs may contribute to disease pathogenesis. A major bottleneck in understanding the mechanisms behind the neurotoxicity of pathological forms of Tau is the lack of genetically tractable models that can recapitulate the effects of Tau PTMs in a short time frame without artifacts associated with Tau overexpression.MethodHuman 0N4R Tau (wild type) was expressed in touch receptor neurons through single‐copy gene insertion. Mutations were introduced into the single‐copy tau transgene through CRISPR‐Cas9 genome editing, including T231E and T231A, to mimic phosphorylation and phospho‐ablation of a commonly observed pathological epitope, respectively, and K274/281Q, to mimic disease‐associated lysine acetylation. We then assessed their impact on age‐dependent response to light touch, neurodegeneration, and mitochondrial parameters such as abundance, morphology, trafficking, and turnover, using fluorescent biosensors including mito‐mKeima.ResultUnlike existing tau overexpression models, C. elegans single‐copy expression of wild type human tau did not elicit overt pathological phenotypes at baseline. However, strains expressing disease associated PTM‐mimetics (T231E and K274/281Q) exhibited reduced touch sensation and neuronal morphological abnormalities that increased with age. Remarkably, the PTM‐mimetics selectively impaired mitophagy following mitochondrial oxidative stress, but had no effect on macroautophagy, and furthermore reduced mitolysosomal trafficking.ConclusionSingle copy expression limits pathological phenotypes to strains expressing disease‐associated Tau mutants. In addition to overt pathology, these mutants eliminate oxidative stress‐induced mitophagy and reduce trafficking of mitolysosomes. Our findings highlight a selective mechanism through which disease‐associated Tau PTMs may suppress compensatory responses to mitochondrial stress that occur with age and provide a new perspective into the pathogenic mechanisms underlying AD.
Ensemble approach for early detection and classification of stages of Alzheimer’s disease
Authors: C R Nagarathna , M M Kusuma 
Published: December 2022

AbstractBackgroundThe proposed model is applied to MRI dataset collected from ADNI and kaggle dataset.MethodWe propose an ensemble model that is combination of VGG19 and additional layers of deep neural networking with a specific configuration for feature extraction and classification.ResultReceived 93.4% of accuracy for ADNI dataset and 95.52% of accuracy for kaggle datasetConclusionWe done our Experiments with MRI dataset collected from ADNI and kaggle and performance metric values are compared. It shows that proposed model gives most promising result for both datasets It is considered to be a high performance model.
Importing implementation methods in clinical dementia research
Authors: Grazia Alice 
Published: December 2022

AbstractBackgroundBringing clinical innovation from dementia research to health‐care requires implementing new courses of action. Implementation science methods can help bridge the gap between biomedical research and clinical practice. We imported implementation methods to perform a feasibility analysis for implementing the clinician’s Uniform Dataset‐cUDS as a standard cognitive assessment in two contexts: European academic memory clinics and Italian academic and non‐academic memory clinics.Method33 questions, addressing centers' contextual factors, mechanisms of impact, acceptability, hurdles and facilitators were posed to academic and non‐academic memory clinics. The Process Evaluation framework was used as a guidance to evaluate implementation feasibility. Mixed‐methods analyses were performed with SPSS and MAXQDA. We labelled open answers into categories and performed proportion tests for each hurdle and facilitator in both contexts.Result46 EADC (European Alzheimer’s' Disease Consortium) academic and 62 SINDem (Italian Society of Neurology on Dementia)(30 academic, 32 non‐academic) clinicians answered the survey. Acceptability towards implementation of cUDS was 65% among EADC and 95% among SINDem responders (p = .134,ɑ = .05). A statistically significant (p = .01) proportion of SINDem clinicians (47%) reported to envision no barrier to the implementation, as compared to EADC clinicians (11%). 59% of EADC centers reported to receive full reimbursement for cognitive assessment versus only 10% in Italian academic centers(p = .58). Qualitative analysis showed similar barriers as the unavailability of material (e.g., local norms) and finances (e.g., insurance, salary) in both EADC‐SINDem centers. Despite non‐statistical significant differences, compared to EADC, SINDem clinicians showed a trend towards greater need of neuropsychologists/specialized staff (EADC: 6%; SINDem: 14‐25%),in particular among non‐academic centers. On the other hand, EADC clinicians seemed more concerned with logistics (EADC: 15%; SINDem: 3%).ConclusionOur analysis revealed a good level of feasibility and acceptability for cUDS in Europe, especially in Italy which has no prior local standard as compared to other European countries (e.g., Germany, Netherlands). Similar barriers were identified among Europe and Italy, however, facilitators seemed to be more specific of the country and setting of implementation. This data also revealed structural hurdles, like heterogeneous reimbursement levels for cognitive assessment. Overall, country‐based feasibility analysis are necessary before proceeding into implementation.
Resolving neuroinflammation in AD
Authors: Plath Niels , Balice‐Gordon Rita 
Published: December 2022

AbstractBackgroundHuman genetics point towards a key role of microglia and microglia expressed genes like TREM2 in neuroinflammation and AD pathology, yet our understanding of microglia spatial and temporal dynamics, therapeutic directionality and translational biomarkers remains limited.Method and ResultsMuna Therapeutics applies structural biology, computational chemistry and human IPSC derived cell assays to develop small molecule agonists for microglial drug targets including TREM2. Introduction of human mutations allows specific drug – target interactions to be probed and has revealed novel small molecule binding pockets, enabling optimized drug design. To identify novel drug targets involved in neuroinflammation, we have built an all‐in‐human spatial transcriptomics and bioinformatics‐based discovery and validation platform. We have assessed >50 human brain samples for pathology‐induced changes in gene expression in microglia and other cells from samples with AD pathology from patients with and without cognitive impairment. This approach has revealed patterns of differentially expressed genes and pathways in brains linked to pathological hallmarks such as Ab plaques and tau tangles, as well as to resilience to the effects of these pathologies. Candidate targets and mechanisms are tested for their impact on neuroinflammation, including directionality, in humanized model systems that also enable translational biomarker discovery and validation.ConclusionAt Muna Tx, state‐of‐the‐art target discovery and validation as well as structural biology and computational chemistry platforms enable microglia targeted drug discovery and can accelerate therapeutic advancement to clinical development.
Relevance of the pre‐clinical models in TBI
Authors: Crawford Fiona ,   Roskamp Institute TBI Research Team
Published: December 2022

AbstractIn the absence of any effective translation from preclinical models to clinical application, what has been achieved by laboratory models of TBI? Analysis and assimilation of results from preclinical TBI studies is confounded by the heterogeneity of the models and the TBI paradigms employed. Variance in animal, injury location, severity, number, frequency, age of animal at injury and age of animal at analyses, not to mention the research focus of the investigators themselves, all contribute to the difficulties in data integration and interpretation. Nonetheless, preclinical TBI research has identified areas of focus and enabled creation of timelines of TBI pathobiology. Ultimately, validation of any potential therapeutic targets will require exploitation of the heterogeneity of preclinical models in order to facilitate clinical translation, given the heterogeneity of the patient population.In the course of modeling TBI paradigms in (primarily) mouse models, the failure of recapitulation of TBI‐dependent neurodegenerative pathology representing AD, PD, ALS etc. has prompted the use of mouse models of neurodegenerative disease, expressing genetic risk factors or humanized for proteins implicated in human neurodegenerative diseases, in efforts to understand how TBI can exacerbate or even precipitate the neurodegenerative pathobiology. These investigations have generated many interesting observations, not always easily consolidated into any clear pathogenic mechanism, but some overarching themes have emerged. Some of the published TBI approaches, and findings, will be reviewed, and knowledge gaps and future directions will be discussed.
Methodological strengths and weakness of cohorts and administrative data for developing population estimates of dementia
Authors: Dobson Annette J , Almeida Osvaldo P , Anstey Kaarin J. , de Crespigny Fleur , Fitzgerald Patrick , Vu Thao Anna , Waller Michael , Flicker Leon 
Published: December 2022

AbstractBackgroundThere are three main methods of obtaining population data on the incidence and/or prevalence of dementia: cross‐sectional surveys (which may be repeated over time); cohort studies that follow people initially without dementia and count newly diagnosed cases over time; and administrative health records (including linkage of records from multiple sources). The major challenges for all these methods are: how well the study sample represents the target population, the accuracy of diagnoses, and the costs of maintaining the data collection over time.MethodIn a project to improve Australia’s dementia statistics, we conducted a series of studies to compare population estimates of dementia obtained using different methods. Firstly, we used existing general health studies of community‐based cohorts, supplemented by linkage to administrative records of hospital and emergency department admissions, assessments for aged care support, medication prescriptions, and death certificates to estimate the cumulative incidence of dementia. Secondly, we created cohorts based on administrative records for entire populations. Thirdly, we assessed the validity of the identification of people with dementia in the record linkage cohorts in various ways, including linkage with studies that had obtained clinical diagnosis through the standardised assessment of participants.ResultWe will present empirical results illustrating the strengths and limitations of these different approaches. In summary, community‐based cohort studies lack representativeness of national or regional populations due to recruitment biases and differential loss to follow‐up. Cohort studies are also costly to maintain over the long time needed for participants to develop dementia. In contrast, the use of administrative records is relatively inexpensive, but is subject to policy changes that impact on the continuity of data coverage and quality. Population coverage may also be problematic for administrative data if important sources of care for people with dementia are not included; for example, in Australia linkable primary care data are not available. The validation studies showed that accuracy was highly dependent on data sources, and identification of dementia type was unreliable.ConclusionPrevalence and trends data of dementia obtained from multiple sources are needed to provide accurate population estimates, together with detailed contextual knowledge and careful analysis.
Efficacy in linguistic characteristics: I‐CONECT project
Authors: Chen Liu , Asgari Meysam , Dodge Hiroko H 
Published: December 2022

AbstractBackgroundResearchers have documented ample evidence suggesting progressive decline in linguistic and syntactic abilities due to cognitive decline. Among measures of syntactic complexity derived from natural language processing (NLP) approaches, we hypothesized that the number of
coordinated phrases
(CPs, an indicator of sentence complexity) would improve from an intervention which intended to enhance cognitive function by providing social interactions through frequent video‐chats.MethodIn the I‐CONECT project, the experimental group engaged in a high dose of semi‐structured conversations (four times per week) via video‐chats, with additional weekly 10 minutes telephone check‐ins. The control group received only the weekly telephone check‐ins. We analyzed language samples derived from the weekly phone check‐ins (WPCs) in this study. WPCs mainly ask about social activities engaged by the participant during the previous week with some semi‐structured open‐ended questions. Out of 186 subjects who were randomized to the trial, 113 subjects had at least one recording of WPCs with sufficient recording quality during the 2nd, 3rd and 4th weeks of the intervention (baseline) and during the 3 weeks (i.e., 22, 23, 24th) before the month 6 (M6) assessments. We extracted the number of CPs from WPCs of 52 experimental (25 MCI, 27 normal) and 61 control (34 MCI, 27 normal) participants. We regressed CP scores at M6 on age, gender, years of education, the experimental (vs. control) group, controlling for baseline CP scores using a linear regression model.ResultAmong the MCI group, the experimental group’s CP scores were 0.60 points higher than the control group (p = 0.046) at M6, which is equivalent to over 10 years of age difference in CP scores (i.e., ‐0.055×10 = ‐0.55), controlling for covariates listed above (see Figure 1). Among those with normal cognition, we did not find any significant differences between the two groups at M6 (p = 0.414).ConclusionWe found that an indicator of sentence complexity improved among the experimental group compared with the control group among the MCI participants. Our results indicated that language measures are capable of tracking clinically meaningful changes in language samples capitalizing their potential use in clinical trials as automated outcome measures.
Social engagement intervention increases dorsal attention network functional connectivity in socially‐isolated older‐old adults: I‐CONECT
Authors: Pruitt Patrick J , Lahna David , Schwartz Daniel L , Peltier Scott , Silbert Lisa C , Dodge Hiroko H 
Published: December 2022

AbstractBackgroundSocial engagement represents a promising intervention to improve or maintain cognitive function, however the neurobiological mechanism through which social engagement impacts cognitive aging remains unclear. Large‐scale cognitive brain networks facilitate cognitive function and represent a set of likely candidates for being affected by social engagement interventions.Using resting‐state functional magnetic resonance imaging (rs‐fMRI) data from the Internet‐Based Conversational Engagement Clinical Trial (I‐CONECT), we investigated the effect of social engagement intervention on functional connectivity within large‐scale cognitive brain networks, specifically the default mode network (DMN), salience network (SAL), frontoparietal network (FPN), and dorsal attention network (DAN).MethodDue to COVID‐19 pandemic, out of 186 randomized participants in the trial, 15 participants were able to complete rs‐fMRI both at baseline and six‐month follow‐up: six participants from the intervention arm (five women; mean age±SD: 79.0±3.8 years) and nine participants from the control arm (six women; 81.2±5.2 years). Nine participants had mild cognitive impairment; six had normal cognition.Intervention effect was calculated in separate regression models for within‐network connectivity of each brain network, with intervention group predicting connectivity at six‐month follow‐up, controlling for baseline connectivity, age, sex, site, and in‐scanner motion.ResultIn examining the intervention effect on DAN connectivity, the overall regression model was statistically significant (R2= 0.867, p = 0.004; Table 1): The experimental group had significantly higher DAN connectivity at follow‐up (b = 0.25, 95% CI: 0.03 – 0.47, p = 0.031) compared with the control group, (for group x time graph using residualized connectivity values, see Figure 1). Overall regression models for DMN, SAL, and FPN networks were not statistically significant (p > 0.1).ConclusionAs social engagement interventions emerge as an effective approach to improving cognition in older adults, this work provides novel insight into the impact of such an intervention on large‐scale cognitive brain network connectivity. Specifically, participants who underwent the intervention showed greater DAN connectivity at follow‐up than control participants. The voluntary directed attention facilitated by the DAN is an integral part of social engagement, and this work suggests that DAN merits additional focus in investigations of social behavior in cognitive aging. These findings must be interpreted with caution, due to small sample size.
Astrocytes in Neurodegenerative Disorders
Authors: Escartin Carole 
Published: December 2022

AbstractAstrocytes are key partners for neurons in the brain. Under pathological conditions, such as neurodegenerative diseases, astrocytes change and become reactive. Even if this response was described more than a hundred years ago, many questions remain about how the reactive state of astrocytes is controlled, and how it impacts their homeostatic functions and surrounding cells.We have developed molecular tools to modulate and monitor reactive astrocytes in situ, and shown that these cells have multiple and context‐dependent effects in neurodegenerative diseases.We further aim to identify new molecular targets to promote neuroprotective functions in reactive astrocytes and identify astrocyte‐based biomarkers for brain diseases.
The Interface Of Delirium And Dementia
Authors: Inouye Sharon K. 
Published: December 2022

AbstractBackgroundWhile delirium and dementia are the most common causes of cognitive impairment in older populations, their interrelationship is complex and poorly understood. Dementia is the leading risk factor for delirium, and delirium is an independent risk factor for subsequent dementia. The current evidence for the inter‐relationship of delirium with Alzheimer’s disease and related dementias (AD/ADRD) will be reviewed in detail.MethodsDr. Inouye will present an overview of the evidence of the inter‐relationship between delirium and AD/ADRD, including epidemiologic, clinicopathologic, biomarker and mechanistic evidence. Previous studies have shown that 2/3 of persons with ADRD will have at least one hospitalization each year, and 50% will have 2 or more; these hospitalizations are associated with a high risk of delirium. Emerging evidence provides strong support for shared and potentially synergistic pathophysiologic linkages between delirium and ADRD. Key questions to be addressed include: Does pre‐existing AD pathology increase vulnerability to delirium? Does delirium accelerate the pace of cognitive decline in those with AD and ADRD?Results and ConclusionsAt the conclusion of this presentation, participants should be able to:–Identify the key features of delirium and effective prevention strategies–Understand the contribution of delirium to worsened cognitive trajectories and outcomes in persons with and without dementia–Recognize potential shared pathophysiologic pathways between delirium and dementia–Appreciate that delirium represents an important preventable contributor to dementia
Clinical outcomes of older persons and persons with dementia admitted for COVID‐19: findings from the Philippine CORONA Study
Authors: Anlacan Veeda Michelle M , Piamonte Bernadeth Lyn C , Sy Marie Charmaine C , Jamora Roland Dominic G ,   The Philippine CORONA Study Group, Espiritu Adrian I 
Published: December 2022

AbstractBackgroundThe coronavirus disease 2019 (COVID‐19) pandemic substantially threatens the health of all populations worldwide, but even more so of vulnerable groups. In our subanalysis of The Philippine CORONA Study, we aimed to determine the impact of older age and dementia on clinically relevant outcomes in COVID‐19 patients.MethodWe included data that were collected in The Philippine CORONA Study, a multicenter, comparative, retrospective, cohort study of 10,881 adult COVID‐19 patients who were admitted between February 2020 and December 2020. Clinical outcomes analyzed were mortality, respiratory failure, duration of ventilator dependence (DVD), intensive care unit (ICU) admission, length of ICU stay (LICUS), and length of hospital stay (LHS) among older persons (individuals ≥ 60 years old) and persons with dementia admitted for COVID‐19 infection.ResultThe adjusted hazard ratios (aHRs) for mortality among the mild and severe cases were significantly higher by 3.93, 95% CI [2.81, 5.50] and by 1.81, 95% CI [1.43, 2.93], respectively, in older patients compared to younger adults. The aHRs for respiratory failure in the elderly were significantly increased by 2.65, 95% CI [1.92, 3.68] and by 1.27, 95% CI [1.01, 1.59] among the mild and severe cases, respectively. The aHR for ICU admission in the older group was significantly higher by 1.95, 95% CI [1.47, 2.59] among the mild cases. Older COVID‐19 patients had significantly shorter median DVD and LHS than younger patients. The aHRs for mortality and ICU admission in persons with dementia were significantly higher by 7.25, 95% CI [2.67, 19.68] and by 4.37, 95% CI [1.08, 17.63], respectively, compared to those without dementia. The group with dementia had a significantly longer median LHS than the group without dementia.ConclusionOlder age and dementia significantly increased the risk of mortality, respiratory failure, and ICU admission among COVID‐19 patients.