bluuebunny/crossref_metadata_2025_split huggingface dataset:
Preliminary analysis of verbal and nonverbal indicators of episodes of lucidity in advanced AD/ADRD
Authors: Dillon Kayla , Fehland Jess , Botsch Meghan , Coulson Alison , Benson Clark , Block Laura M , Gilmore‐Bykovskyi Andrea L 
Published: December 2023

AbstractBackgroundAlzheimer’s disease and related dementias (ADRD) are progressive neurodegenerative diseases believed to cause irreversible cognitive and functional losses. Episodes of lucidity (ELs) are described broadly as spontaneous and unexpected return of abilities believed to have been lost in individuals living with advanced ADRD.1 These events have been qualitatively identified by caregivers and healthcare staff but have yet to be quantitatively described.1 This study aimed to measure potential quantitative verbal/nonverbal indicators of ELs in individuals living with advanced ADRD.MethodFive participants living with advanced ADRD in a regional hospice unit were enrolled, from which 281 hours of audiovisual data were collected. A behavioral coding scheme captured potential verbal/nonverbal indicators that may characterize lucid events. Indicators were coded (timed‐events) independently by two coders using Observer XT. Descriptive statistics for verbal/nonverbal indicators of ELs included: indicator frequency, rate, duration, and proportion. Additionally, we compared descriptive statistics for verbal/nonverbal indicators in high‐likelihood ELs identified by the research team, caregivers, or hospice staff to verbal/nonverbal indicators in the participant’s baseline typical behavior with similar stimuli.ResultTen potential ELs were identified by the research team, with three of these episodes endorsed by caregivers and hospice staff. For endorsed ELs, the average proportion and duration of all coded indicators was greater than that of their respective comparators, except for three nonverbal indicators (shakes head, manipulates object, directed attention). The average rate and frequency of all coded indicators was greater than that of their respective comparators, except for two nonverbal indicators (shakes head, directed attention).ConclusionOur preliminary analyses found that a comparative analysis approach to characterizing ELs provides an opportunity to identify substantial variability of potential ELs from individual baseline. While verbal/nonverbal indicators were generally more frequent/intense during ELs, this was not always true. Given the current lack of a formal definition for ELs, efforts to identify and characterize the content of ELs benefit from triangulation across event indicators with qualitative data collected from informants.
References:[1] Mashour GA, Frank L, Batthyany A, et al. Paradoxical lucidity: A potential paradigm shift for the neurobiology and treatment of severe dementias. Alzheimers Dement. 2019;15(8):1107‐1114. https://doi.org/10.1016/j.jalz.2019.04.002
The Alzheimer’s Disease Sequencing Project – Follow Up Study (ADSP‐FUS): APOE genotype status and demographic characteristics across datasets
Authors: Mena Pedro R. , Zaman Andrew , Faber Kelley M. , Adams Larry D. , Inciute Jovita D. , Whitehead Patrice , Foroud Tatiana M. , Reyes‐Dumeyer Dolly , Kuzma Amanda B , Nicaretta Heather Issen , Naj Adam C. , Martin Eden R. , Dalgard Clifton L. , Schellenberg Gerald D. , Wang Li‐San , Mayeux Richard , Vardarajan Badri N , Vance Jeffery M. , Cuccaro Michael L. , Kunkle Brian W. , Pericak‐Vance Margaret A. 
Published: December 2023

AbstractBackgroundThe ADSP‐FUS is a National Institute on Aging (NIA) initiative focused on identifying genetic risk and protective variants for Alzheimer Disease (AD) by expanding the ADSP beyond non‐Hispanic Whites of European Ancestry (NHW‐EA) populations. Given the lack of diversity in the ADSP, the ADSP‐FUS was designed to whole genome sequence (WGS) existing ethnically diverse and unique cohorts. The upcoming phase ADSP‐ FUS 2.0: The Diverse Population Initiative, focuses on inclusion of Hispanic/Latino (HL), non‐Hispanic Black with African Ancestry (NHB‐AA), and Asian populations.MethodsADSP‐FUS cohorts consist of studies of AD, dementia, and age‐related conditions. Clinical classifications are assigned based on standard criteria from clinical measures and history, as well as additional neuropathologic data. In addition to production of WGS, genome‐wide array and APOE genotyping is acquired or performed for all ADSP‐FUS samples.ResultsThe ADSP‐FUS currently consists of 38 cohorts comprised of ∼40,000 individuals, with plan to sequence >100,000 individuals from diverse ancestries. Genotyping, sequencing, and clinical adjudication has been performed on 23,428 participants (cases N = 6,961, median age = 73; controls N = 13,007, median age = 72; ADRD N = 3,460, median age = 77. More participants are female (62.3%) than male and are evenly distributed across cases (61.0%), controls (63.1%), and ADRD (61.8%). As expected, the most prevalent APOE genotype is APOE 3/3 (% by cases/controls for 2/2 = 0.2,0.4; 2/3 = 4.3, 8.2; 2/4 = 2.2, 1.8; 3/3 = 43.8, 64.4; 3/4 = 39.5, 23.0; 4/4 = 10.1, 2.2). These proportions vary greatly between ethnicities, with the highest for APOE 4/4 observed in Asian participants (8.8%) and the lowest in Hispanic participants (2.5%), for example. Mean Braak stage for AD cases is higher (5.1+1.2) than controls (2.6+1.3) and ADRD participants (3.5+1.6).ConclusionThe results provide an overview of features of ADSP‐FUS cohorts. As the ADSP‐FUS expands in size and diversity, this genomic resource, available via NIAGADS, will be integrated with ADSP programs focused on phenotype harmonization, association analyses, functional genomics, and machine learning. In concert with these programs, the ADSP‐FUS will accelerate the identification and understanding of potential genetic risk and protective variants for AD across all populations with the target of developing new treatments that are globally effective.
SARS‐CoV‐2 infection worsens Vascular Dementia (VaD)‐associated neuropathology in mice
Authors: Gressett Timothy E , Biose Ifechukwude Joachim , Narayanappa Amruta , Ismael Saifudeen , Talkington Grant , Bix Gregory J 
Published: December 2023

AbstractBackgroundVascular Dementia (VaD) is the second leading cause of dementia behind Alzheimer’s disease (AD) and has a profound association with the morbidity and mortality of COVID‐19. Recent evidence demonstrates that preexisting vascular dementia is associated with increased COVID‐19 incidence and worsened outcomes after COVID‐19 infection. Collectively, these observations suggest that vascular pathology in VaD such as blood‐brain barrier (BBB) disruption, directly contributes to this association. Previously we and others have demonstrated that SARS‐CoV‐2 binds to the vascular integrin α5β1 receptor and that inhibition of α5β1 integrin with the clinically‐validated peptide ATN‐161 can improve acute SARS‐CoV‐2 infection and reduce SARS‐CoV‐2‐mediated vascular disruption. Furthermore, we have previously demonstrated that ATN‐161 reduces BBB disruption in models of brain ischemia (stroke) and VaD‐modeled chronic bilateral carotid artery stenosis (BCAS), which models reduced blood flow, BBB disruption, neuroinflammation, white matter damage and cognitive decline in VaD. In the present study, we tested the hypothesis that experimental VaD worsens COVID‐19‐associated neuroinflammation and exacerbates subsequent neurovascular damage, which may be targeted therapeutically by ATN‐161.Method10‐week‐old wild‐type (WT) BALB/c male mice were infected with 2×105 PFU mouse‐adapted (MA10) SARS‐CoV‐2 or mock infection 1‐week after BCAS surgery to model the effects of preexisting VaD in mice and subsequent SARS‐CoV‐2 infection. Body weight was monitored daily. The brain was isolated 3‐days post‐infection (dpi) and analyzed for immunohistochemical and mRNA expression of selected markers of neuroinflammation and immune response.ResultBCAS+SARS‐CoV‐2 infected mice exhibited a significant reduction in body weight at 3 dpi compared with the BCAS+mock infected group. Immunohistochemical analysis demonstrated a significant increase in α5 integrin signal in the cortex. SARS‐CoV‐2 infection after BCAS worsened brain and vascular inflammation and glial activation, indicated by increased Iba‐1 (microglia) and GFAP (astrocyte) immunofluorescence and brain (proinflammatory) IL‐1β cytokine transcript levels. Lastly, SARS‐CoV‐2 infection worsens white matter (myelin) integrity as measured by myelin basic protein (MBP) immunofluorescence.ConclusionSARS‐CoV‐2 aggravated VaD‐associated morbidity indicated by elevated white matter damage, glial activation, and neuroinflammation along with increased integrin α5 expression. Integrin α5β1 could, therefore, be a therapeutic target for improving both acute SARS‐CoV‐2 infection, and VaD post‐COVID morbidity and cognitive decline.
Network Understanding of Genetic Interplay Between Alzheimer’s Disease Endophenotypes
Authors: Keegan Stephen , Cary Gregory A. , Wiley Jesse C , Gockley Jake , Leal Karina , Butler Robert R. , Greenwood Anna K , Carter Gregory W ,   The Emory‐Sage‐SGC TREAT‐AD Center
Published: December 2023

AbstractBackgroundAlzheimer’s disease (AD) therapeutics have largely been unsuccessful in alleviating disease burden in those afflicted by the disease. The TREAT‐AD Consortium is an international group of academic researchers dedicated to identifying novel molecular targets for AD from underexplored areas of disease linked pathology.MethodWe generate 19 disease biology specific networks, Biological Domains (biodomain), from pathway reconstructions based on interactions from pathway databases. The networks are composed of gene lists which represent Gene Ontology terms (GO Terms) that best describe AD endophenotypes. We interrogate these networks to identify plausibly causal genes using a weighted Key Driver Analysis (KDA). The networks are also used as priors for training Graph Neural Networks (GNN) on transcriptomic data.ResultBecause a biodomain network object has genes and GO Terms that are annotated to other biodomains, we inferred inter‐biodomain relationships. Analysis of the directed biodomain network provided predictions of the ordering of processes that contribute to AD progression. Molecular targets inferred to be causal across multiple biodomains provide druggable targets that are upstream of AD‐correlated processes. For example, we found gene expression changes in the lipid metabolism biodomain that are driven by genes annotated to autophagy and immune response.ConclusionAlzheimer’s Disease biology can be subdivided into networks which represent processes that are notable to AD patients. Genes from these networks will be prioritized to identify candidate therapeutic targets that are well situated to affect the network biology. TREAT‐AD investigators will validate these targets in cell models and generate experimental resources to support further target development.
Development of system for assessing neurologic impact of long COVID‐19 and post‐COVID‐19 vaccination symptoms
Authors: Ruchisrisarod Chanida 
Published: December 2023

AbstractBackgroundThe coronavirus disease (COVID‐19) pandemic has had a global impact on health. Some patients experience persistent symptoms even after the infection has cleared. The virus affects the body’s inflammation system, potentially leading to brain and organ damage. This study aims to develop a tool to assess the impact of COVID‐19 infection and vaccination, as well as the inflammatory response in patients with Long COVID and those who reported symptoms after receiving various COVID‐19 vaccines.MethodPatients who report prolonged symptoms after contracting COVID‐19 or significant symptoms after receiving various types of vaccines will be assessed, including serological testing to detect antibodies against the virus, cytokine profiling, biomarkers for neurodegenerative diseases (plasma levels of amyloid beta, glial fibrillary acidic protein and neurofilament light hain) and clinical symptoms. The study will investigate the association of evidence of ongoing active brain injury, biomarkers, elevations of pro‐inflammatory cytokines, and the presence of autoantibodies to various antigens.ResultThe study comprised 85 participants, including 50 with long COVID‐19, 30 of whom presented with neurological symptoms and 20 with non‐neurological symptoms, and 35 who reported post‐vaccination symptoms, 11 of whom had neurological symptoms and 24 had non‐neurological symptoms. Participants underwent the proposed assessment system, with 33 having completed their first follow‐up evaluation, and 3 having completed their second evaluation.ConclusionWe present our initial findings from our proposed assessment system for evaluating the impact of long COVID‐19 and post‐vaccination symptoms. The results of this study aim to provide insight into the lasting effects of COVID‐19 and the potential impact of COVID‐19 vaccinations on patients. The full results of this study will be reported in due course.
COGNITIVE IMPAIRMENT AFTER THE DIAGNOSIS OF LATE‐ONSET EPILEPSY ‐ A SYSTEMATIC REVIEW
Authors: Chamoun Joelle , De Almeida Ribeiro Margaux , Contenseaux Coralie , Mockler David , Moroni Christine , Chen Yaohua Sophie 
Published: December 2023

AbstractBackgroundThe management of late‐onset epilepsy in older people (LOE) is often suboptimal despites its high incidence. The impact of LOE is not only epileptic, it also leads to multiple consequences, such as cognitive decline, and other geriatric syndromes. Cognitive decline, as one of the major consequences of LOE, causes in turn deterioration in quality of life and loss of autonomy. However, the effect of de novo LOE on cognitive decline without dementia in older people remains poorly understood. Similarly, very few studies have analysed the risk factors associated with cognitive decline. Therefore, we conducted a systematic review to describe the long‐term effect on cognition of LOE on older people, including the incidence of cognitive decline after the diagnosis of LOE and the associated risk factors.MethodAccording to PRISMA 2020 guidelines, we searched 5 electronic databases (“EMBASE”, “Medline”, “CINAHL”, “PsycINFO”, “Web of Science”) for articles published until 27th Oct 2022. The criteria selected were patients “60 years old and older” with “late onset epilepsy” diagnosis and “cognitive decline” or “cognitive impairment”, whom do not have known brain tumor or a posttraumatic etiology. Four researchers independently screened studies based on the title and abstract, then by full text. Data extraction was done through “Covidence” platform with each study being processed by two reviewers and conflicts were solved by a third reviewer.ResultWe selected 26 out of 326 initially retrieved publications based on full text review. Most of the studies conducted so far however did not take into consideration or did not control for the baseline cognitive status of their patients before or at the onset of epilepsy and therefore could not objectively determine the real burden of late onset epilepsy on cognitive impairment in this population.ConclusionData in favour of a causal relationship between late onset epilepsy and cognitive decline in elderly with no known baseline cognitive impairment is still precarious. More studies should be conducted with more specific assessment tools that could permit us to have a better estimate of the burden of LOE on cognition such for example imaging and neuropsychological assessment before and after the incidence of epilepsy.
Transcriptomic similarities in vulnerable and resilient brain regions of Parkinson’s disease and Alzheimer’s disease
Authors: Siebert Marina , Carello‐Collar Giovanna , Bastiani Marco Antônio De , Zimmer Eduardo R 
Published: December 2023

AbstractBackgroundParkinson’s disease (PD) and Alzheimer’s disease (AD) share multiple pathophysiological features but affect different brain regions. While the hippocampus is highly vulnerable in AD, the loss of dopaminergic neurons in the substantia nigra (SN) is a hallmark of PD. By contrast, other brain regions, such as the cerebellum, seem resilient to neurodegenerative processes in both diseases. However, the biological mechanisms driving brain regional vulnerability and resilience to neurodegeneration in PD and AD remain elusive. Here, we aimed to analyze the transcriptomic profiles of PD and AD in vulnerable (VR) and resilient (RR) brain regions.MethodPD and AD datasets were obtained from the Gene Expression Omnibus public data repository (PD: GSE28894, GSE20186, GSE20314, GSE42966, GSE49036, GSE54282, GSE20164, GSE20163, and GSE8397; AD: GSE118553, GSE44768, GSE036980, GSE084422, GSE1297, GSE29378, and GSE48350). Hippocampal, SN, and cerebellar differential expression analysis was performed to identify differentially expressed genes (DEGs) for each disease versus age‐matched controls. Functional enrichment analysis (FEA) was accomplished to identify similar signatures in VR and RR in PD and AD. Analyses were performed using the R (adj p‐value <0.05).Result607 DEGs overlapped in the VR of PD and AD, while 1780 DEGs in the RR. FEA revealed 114 gene ontology (GO) terms shared between the VR and 276 GO terms overlapping between PD and AD RR. The GO terms were assembled in clusters of biological processes (Table 1). Cluster observation suggests that both VR and RR share similar enriched processes, such as “cellular respiration”, “regulation of neuron death”, “catabolic pathways”, “response to injury and DNA damage”, and “exocytosis and neurotransmitter secretion”. By contrast, “regulation of cell growth”, “response to steroid hormones”, and “regulation of nervous system development” were unique for the RR, while “membrane lipid metabolic process” and “regulation of cell communication” clusters were found only in the VR.ConclusionOur results highlight a transcriptomic landscape shared by PD and AD in both VR and RR. Looking at the similarities between brain regions vulnerable and resilient in different neurodegenerative diseases may contribute to the understanding of their pathogenesis and clinical course, as well as guide the development of therapeutic strategies.
Plasma biomarkers of tau for the differentiation between slow and fast tau‐PET accumulators
Authors: Tissot Cécile , Therriault Joseph , Rahmouni Nesrine , Servaes Stijn , Macedo Arthur C. , Wang Yi‐Ting , Stevenson Jenna , Snellman Anniina , Rodriguez Juan Lantero , Stevenson Alyssa , Arias Jaime Fernandez , Lussier Firoza Z , Chamoun Mira , Mathotaarachchi Sulantha , Bezgin Gleb , Kunach Peter , Triana‐Baltzer Gallen , Gauthier Serge , Karikari Thomas K , Kolb Hartmuth C. , Benedet Andrea Lessa , Blennow Kaj , Zetterberg Henrik , Pascoal Tharick Ali , Ashton Nicholas J. , Rosa‐Neto Pedro 
Published: December 2023

AbstractBackgroundPlasma markers of tau are currently being studied as proxies of cerebral neurofibrillary tangle (NFT) accumulation. Phosphorylated tau (pTau) and N‐terminal tau fragment (NTA) assays are associated with present and future tau‐PET load. Our aim was to investigate whether plasma markers could predict whether someone will be a slow or fast accumulator.MethodWe assessed 143 individuals [72 CU, 54 MCI, 17 AD] from the TRIAD cohort, with two available [18F]MK6240 tau‐PET scans and calculated the relative change (Δ[18F]MK6240) between baseline and follow‐up [mean follow‐up time: 2.1 ± 0.7 years]. We used tertiles to divide individuals as slow, medium and fast accumulators. Additionally, we measured baseline plasma pTau181, pTau217, pTau231 and NTA concentrations. We computed the effect size (Cohen’s d) and area under the curve (AUC) for each plasma marker for Δ[18F]MK6240 between slow and fast accumulators. Δ[18F]MK6240 was calculated in Braak stages I/II, III/IV and V/VI.ResultWe first observed that the highest effect size for Δ[18F]MK6240 in Braak I/II was depicted by pTau231. For Δ[18F]MK6240 in Braak III/IV and Braak V/VI, pTau217 presented the highest effect size (Figure 1). Moreover, AUC values were the highest, and highly similar, in ΔBraak I/II for pTau181, pTau217 and pTau231. For ΔBraak III/IV, pTau181 and pTau217 presented the highest values. Finally, AUC for ΔBraak V/VI, pTau231 and NTA had the highest values, which were also similar (Figure 2).ConclusionPlasma pTau biomarkers (181, 217 and 231) are great predictors of fast accumulation in early to middle Braak regions. For late Braak regions, fast accumulation was best predicted by pTau217 and NTA. Plasma markers are able to determine whether someone will be a fast accumulator in a stage‐specific manner. The currently available tau biofluid measures could be used in the clinical and clinical trial settings, as these are less invasive and cheaper than CSF or PET assessments. Especially in the recruitment phase, pTau217 could be used for screening individuals that are more likely to accumulate tau fast.
Progressive dysregulation of circular RNAs in the hippocampus of a transgenic mouse model of amyloidosis
Authors: Carvalho Lavínia Perquim , Bastiani Marco Antônio De , Carello‐Collar Giovanna , Limberger Christian , Zimmer Eduardo R 
Published: December 2023

AbstractBackgroundCircular RNAs (circRNAs) are a class of RNAs that act as transcriptional regulators. They have a circular structure and are produced from back‐splicing events, which makes them more stable than linear RNAs. In Alzheimer’s disease (AD), the role of circRNAs remains elusive. Here, we aimed to evaluate whether the transcription of circRNAs is altered in the hippocampus, a region highly vulnerable to AD, of a transgenic amyloid mouse model.MethodWe selected hippocampal RNA‐sequencing or microarray datasets of circRNAs of the APPswe/PSEN1dE9, a widely used transgenic amyloid mouse model, from the NCBI databases. CircRNAs were detected with the CIRI2 algorithm by using the gene symbol of the parent transcript and the transcript ID. We identified the differently expressed circRNAs between APPswe/PSEN1dE9 and age‐matched wild‐types using the DESeq2 method (p‐value < 0.01). The packages UpSetR and VennDiagram were used to uncover the circRNAs commonly altered between the studies. All analyses were performed in R.ResultFrom 12 databases, three had hippocampal circRNA data of 4, 6, and 8‐month‐old APPswe/PSEN1dE9 mice (GSE166393; GSE158995; and PRJNA712946, n = 3 per group). Amyloid‐beta (Aβ) starts to deposit at six months in the APPswe/PSEN1dE9 hippocampus. The number of dysregulated circRNAs increased with age: 41 (4‐month‐old), 82 (6‐month‐old), and 425 (8‐month‐old) (Figure 1). Interestingly, only one circRNA was shared between the three studies at all time points, originating from the CCDC141 gene. Additionally, 15 circRNAs were shared in at least two ages, such as CD2AP, FMN1, HOMER1, IL1RAP, NDST3, and TET1 (Please, see the full list of intersections in Figure 2). By dividing groups into pre‐plaque (4‐month‐old) and amyloid (6 and 8‐month‐old) phases, we found that four altered circRNAs were shared in both stages, 37 exclusively in pre‐amyloid stage and 490 in amyloid stage (Figure 3).ConclusionOur results demonstrate an increasing dysregulation in circRNAs profiles in the hippocampus of the APP/PS1 mice. Considering the role of circRNAs as transcriptional regulators, one could argue that these progressive changes may impact gene expression in AD‐related brain regions.