bluuebunny/crossref_metadata_2025_split huggingface dataset:
A systematic evaluation of cortical GABA levels in transgenic mouse models of amyloid
Authors: Ramos Vanessa G. , Carello‐Collar Giovanna , Bellaver Bruna , Ferreira Pamela C.L. , Mensch André Nunes , Pascoal Tharick A. , Rosa‐Neto Pedro , Zimmer Eduardo R 
Published: December 2023

AbstractBackgroundRodent models that overexpress mutations in the amyloid precursor protein (APP) and presenilin 1 (PSEN1) genes have been widely applied in Alzheimer’s disease (AD) research. These models classically present amyloid plaque deposition in cortical and hippocampal areas and neurotransmission changes. Although amyloid‐related glutamatergic abnormalities have been extensively described, little is known about its effects on the GABAergic system. Thus, we aimed to examine GABA levels in the cortex of two transgenic amyloid mouse models.MethodWe systematically reviewed the literature following the PRISMA 2020 guidelines. PubMed and Web of Science databases were searched for studies reporting GABA levels in the cortex of APPswe/PSEN1dE9 and Tg2576 mice. We opted to evaluate only animals with mature amyloid plaques in their cortices, according to each mouse model previous characterization.ResultThe search identified 3576 papers. Seven records met the inclusion criteria (Tg2576: n = 21, mean age ± standard deviation (SD) = 14.7 ± 3.7 months; controls: n = 21; APPswe/PSEN1dE9: n = 25, mean age ± SD = 8.5 ± 4.1 months; controls: n = 25). Five out of seven results reported non‐significant differences in the GABA levels in multiple cortical regions, such as the frontal, pre‐frontal, and rhinal cortices of the Tg2576 mouse model, but two studies described that GABA is significantly decreased. Furthermore, all studies with the APP/PSEN1 model consistently reported decreased cortical GABA levels. Figure 1 provides a summary of our findings.ConclusionOur results suggest that APP and PSEN1 mutations may contribute to the decrease in the levels of GABA in cortical regions of amyloid models. Future meta‐analyses and clinical studies are needed to ascertain the consistency of the reported results.
Exploring the Behaviour, Reliability, and Usability of a new Smartphone Version of Paired Associates Learning
Authors: Kaula Alexander J , Taptiklis Nick , Cormack Francesca K 
Published: December 2023

AbstractBackgroundPAL is a well‐known and trusted task with good sensitivity to deficiencies in memory capabilities. There has been considerable interest in a smartphone version of PAL, and Cambridge Cognition has now completed work on smartphone PAL. Parallel work has shown that this new version of PAL is of equivalent difficulty to the existing classic PAL, and this study addresses characteristics of the smartphone version alone, in a well‐powered within‐subjects study designed to assess test‐retest reliability, bias, and the usefulness of a familiarisation session, as well as exploring usability.MethodWe obtained three PAL scores over three consecutive days in 86 (31 m, 55 f) participants aged 55+ (M = 57.6, SD = 5.65) via the Prolific online platform. Each day participants used their own devices to complete the smartphone PAL task. We analysed adjusted error scores up to eight‐box problems, with participants showing extreme score fluctuations (M +/‐ 3xSD) excluded on the basis that the task was not taken under comparable conditions. We analysed test‐retest reliability using Pearson correlations of scores over the three days and analysed the effect of a familiarisation session by looking at mean scores over three days.ResultsThere was some attrition of users due to technical issues in the prototype version of the task, but adherence was good, and participants reported high levels of task enjoyment and satisfaction. Test‐retest reliability between familiarisation and Day Two was good, r = .63, and very good between Day Two and Day Three, r = .7. Analysis of mean scores showed that the familiarisation session had a significant effect, with task learning between familiarisation and Day Two significantly greater than between Day Two and Day Three. Participants reported good enjoyment of the task, and overwhelmingly described usability characteristics in positive terms.ConclusionThis study highlights the value of a familiarisation session in reducing learning effects, and, like classic PAL, shows good to very good reliability. Moreover, PAL on a smartphone was well‐liked by these older participants, supporting its use in older populations.
Effects of lithium on phosphatidylinositol‐3‐kinase signaling pathways in triple transgenic animals for Alzheimer' disease
Authors: Couto Caíque de Oliveira Portugal , Wagner Carlos , Forlenza Orestes Vicente , De‐Paula Vanessa V.J. 
Published: December 2023

AbstractBackgroundAlzheimer’s disease (AD), a severe, progressive and multifactorial disease. Among the altered biological pathways, we have the phosphatidyl inositol 3 kinase (PI3K), an important cell signaling mediator that loses its function as a result of changes in the Tau protein and Aβ toxicity. Our aim is to determine the ontological pathways related to PI3K in 3xTg‐AD animals chronically treated with lithium at therapeutic and subtherapeutic doses. Also determine the unique, statistically significant proteins of the biological pathways in the ontological pathway altered in hippocampal tissue.MethodThe animals' hippocampus (WT and 3xTg‐AD) were divided into three subgroups: Li0 (standard chow); Li1 (ration containing 1.0 g of lithium carbonate/Kg); and Li2 (ration containing 2.0 g of lithium carbonate/Kg). Primary cultures of hippocampal neurons were treated with doses of 0.02; 0. 2 and 2mM. The identified protein pathways will be compared by Gene Ontology, using ClueGO, a Cytoscape software plug‐in. The analyzes for comparison with neurons and subsequent tissue identification will be performed by ‘Benjamini & Hochberg False Discovery Rate’ (p≤0.05 setting) for test correction for ‘biological process’. Ethical committee (1293/09).ResultOur results on PI3K showed enrichment of pathways: response to hormone, cell migration, cellular response to endogenous stimulus, positive regulation of response to stimulus and regulation of catalytic activity.ConclusionInitial results are promising for the pharmacological understanding of lithium as a neuroprotector for Alzheimer’s disease.
Next generation humanized mice to investigate how Traumatic Brain Injury interacts with ApoE4 genetic risk factor to accelerate dementia
Authors: Khasheeipour Khashayar TK , Brown Arthur , Prado Marco 
Published: December 2023

AbstractBackgroundTraumatic brain injury (TBI) is among the leading causes of disability and has been strongly linked to Alzheimer’s disease (AD), the most prevalent cause of dementia. Patients with a history of repeated TBI can present pathologies and symptoms similar to AD: Tau protein neurofibrillary tangles, Amyloid Beta Plaques, and chronic inflammation. We propose that TBI triggers pathological processes that underlie AD development and thereby accelerates AD’s development and severity.Apolipoprotein E4 (ApoE4) protein has been thought to play a central role in several processes underlying AD development. ApoE4 is one of the biggest genetic risk factors for AD, which is also linked to worse short‐term and long‐term outcomes after TBI. However, how ApoE4 mechanistically affects the development of AD‐pathology after TBI has yet to be understoodMethodTo explore this gap, we will use mice with humanized genes which develop AD like pathology with age (Late‐onset AD). The humanized genes include amyloid precursor protein (hAPP) and microtubule‐associated protein tau (hMAPT) ‐ precursors to amyloid beta plaques and neurofibrillary tangles, respectively ‐ in addition to two copies of apolipoprotein E4 (ApoE4) or the control ApoE3 allele. Half of these mice will experience three mild TBIs modeled after human concussions, while the other half will only be anesthetized. All mice will undergo behavioral testing to measure cognitive deficits and molecular analyses to characterize the timing and severity of AD pathology. Cognitive testing will be carried out using the rodent touchscreen Continuous Performance Test (rCPT), which are widely used with AD patients to test attentional processes.ResultPreliminary results from rCPT before TBI, reveal no significant differences between genotypes and sex at 6‐month of age.ConclusionWe aim to uncover how TBI interacts with ApoE4 protein to accelerate AD pathology at the molecular and behavioral levels. To maximize the clinical relevance of this project, we use mice with human genes implicated in AD, a clinically relevant noninvasive model of concussion, and touchscreen cognitive testing identical to touchscreen testing in humans. We aim to bridge the gap between animal models and clinical settings to identify future therapeutic targets for TBI and AD.
An information‐sharing framework of patient label propagation method to reveal distinct blood biomarkers and signatures in Alzheimer’s disease subgroups
Authors: Huang Xiaoqing , Garfe Nur Jury , Reeves Cristian A Lasagna , Huang Kun , Zhang Jie 
Published: December 2023

AbstractBackgroundAlzheimer’s Disease (AD) is a complex and heterogenous dementia and the early detection remains very challenging. Although progresses have been made to identify serum biomarkers associated with AD, it is still difficult to generalize the findings into clinical setting and trace back to learn how these AD biomarkers are progressed through the regulatory pathways and how they play the roles in the disease mechanisms. Furthermore, distinct patterns or signatures among atypical progressing subgroups has not been investigated.MethodWe defined four subgroups of AD patients based on the trajectories of tauopathy and cognitive decline. Using the blood transcriptomic data from ROSMAP and ADNI, we performed hierarchical clustering for the top 1000 variable genes to obtain the gene signatures in each group. An NMF‐based decomposition and network assisted label propagation method was applied. Finally, we use the inferred label for ADNI patients to assess the distinct progression patterns for each AD subtype and validate and uncovering the genes and their enriched pathways that are associated with flagged progression biomarkers.ResultOur preliminary results show that two gene expression clusters exist for both ROSMAP and ADNI data. Our previous study identified the activation of calcium channel related pathway exhibits a detrimental role in AD, with representative genes such as TGFB1, and S100A12. We observe the same pattern for these two genes in a subset of patients from ADNI gene expression data with an enrichment in neovascularization processes. We are now propagating patient group labels with the prior evidence of the alignment between these two data sets and investigating the primary genes linked to specific biomarker progression patterns through longitudinal analyses.ConclusionWe identified several altered pathways and genes that potentially render atypical AD progression patterns reflected by various biomarkers. Future work is undergoing to further explore the link between the gene signatures in each subgroup and the blood transcriptomic sub‐clusters, as well as the comparisons of the two blood transcriptomic data for potential longitudinal clinical information mapping between the two datasets.
Aβ accumulation associated with executive function decline and tau accumulation associated with memory decline in cognitively normal older people
Authors: Chen Xi , Juarez Alexis , Baker Suzanne L. , Harrison Theresa M. , Landau Susan M. , Jagust William J. 
Published: December 2023

AbstractBackgroundThe early accumulation of Aβ and tau in cognitively‐normal people is predictive of future cognitive decline. It has been difficult, however, to disentangle their effects. Aβ and tau target distinct regions in early stages. Frontal‐parietal regions are among the first to show Aβ accumulation and are important for executive control. Temporal regions, especially the medial temporal lobe, are early sites where tau accumulates and are critical for memory. Their differential vulnerability to Aβ and tau allows us to examine whether there are specific pathology‐cognitive associations, where faster decline in memory, beyond its expected level based on executive function, may be related to tau accumulation, and that faster executive function decline may be related to Aβ accumulation.Method78 cognitively‐normal older adults from the Berkeley Aging Cohort Study underwent longitudinal 11C‐Pittsburgh compound‐B (PiB) PET, 18F‐flortaucipir (FTP) PET, and cognitive assessments of executive function and memory (Fig‐1A). We used linear mixed‐effects models to estimate longitudinal change in Aβ (Fig‐1B), temporal tau (Fig‐1C), executive function (Fig‐1D), and memory (Fig‐1E). We focused on within‐individual variability in cognitive decline in different domains and computed two cognitive decline residual scores (executive function controlling for memory, Fig‐2A; memory controlling for executive function, Fig‐2B) to represent domain‐specific performance decline.ResultAβ accumulation across wide‐spread regions, especially frontal/parietal cortex, was associated with faster executive function decline, but not memory, even after controlling for meta‐temporal tau change (Fig‐3A). On the other hand, temporal tau accumulation, especially in the medial temporal regions, was related to faster memory decline, but not executive function, even after controlling for global Aβ change (Fig‐3B). Using raw cognitive slopes, instead of residual scores, yielded stronger associations with both pathologies but reduced the ability to detect specific pathology‐cognition relationships.ConclusionWe found evidence supporting specific associations between accumulating pathology and domain‐specific cognitive decline. The “Aβ‐executive function, tau‐memory” association may reflect specific vulnerabilities in the executive control network and the memory network to different pathology, leading to cognitive decline in different domains. The variability of cognitive decline within the same individual across different domains provides unique information and may be used as behavioral markers for specific pathology.
Comparing the computerized and standard paper‐and‐pencil version of a novel test of memory in a community‐based geriatric sample
Authors: Beaulieu Ashleigh Nicole , Quintana Alan A , Ortiz Juliana , Ortega Alexandra , Hincapie Diana Maria , Curiel Rosie E , Loewenstein David A. 
Published: December 2023

AbstractBackgroundEarly and accurate diagnosis of Alzheimer’s disease (AD) is critical to improve illness management and outcomes, making neuropsychological measures an essential tool for clinicians. Research has demonstrated that proactive semantic interference (PSI) and failure to recover from PSI (frPSI) are sensitive to cognitive changes in early mild cognitive impairment (MCI) and preclinical AD determined by Aβ load using PET (Loewenstein et al., 2018; Matias‐Guiu et al., 2017; Curiel et al., 2019). These novel constructs are assessed by the LASSI‐L (Crocco et al., 2018; Crocco et al., 2020). The aim of the current study was to compare a new computerized version of this measure, the LASSI‐BC, to the standard paper‐and‐pencil version of the test.Method110 cognitively unimpaired (CU) older adults and 79 older adults diagnosed with amnestic MCI (aMCI) were administered the paper‐and‐pencil form of the LASSI‐L, whereas 62 CU and 52 aMCI participants were administered the LASSI‐BC. Their performance was compared to assess the validity of the LASSI‐BC to discriminate between different diagnostic groups.ResultTo assess the validity of the computerized version, both the aMCI and CU groups were compared using χ2 test for categorical variables and ANOVA for continuous variables, with adjustment for covariates such as degree of initial learning, sex, education, and language of evaluation. The performance of CU and aMCI groups using either form was relatively commensurate. Notably, sensitivity and specificity of measures of PSI and frPSI on both versions were calculated to assess diagnostic validity, yielding the following Results Sensitivity of 86.5%, Specificity of 88.1%, and Overall Classification of 87.4% for the LASSI‐BC relative to a Sensitivity of 65.0%, Specificity of 83.6%, and Overall Classification of 75.8% obtained for the paper‐and‐pencil LASSI‐L.ConclusionThe LASSI‐BC displayed exceptionally high diagnostic validity which was comparable to the well‐established LASSI‐L. Notably, the advantages of the LASSI‐BC include a more standardized administration, suitability for remote assessment, and an automated scoring mechanism that can be verified by a built‐in audio recording of responses. These findings support the LASSI‐BC, a novel computerized assessment, as an exceptional tool for the early identification of individuals at risk of progressing to dementia.
Brain extracellular vesicles from Alzheimer’s Disease and Down Syndrome patients mediate spread of senescence‐like phenotype in vitro
Authors: Bilousova Tina , Melnik Mikhail , Matsuo Yuriko , Kodavatikanti Achyutha , Knitowski Nina , Atluri Swetha , Gylys Karen H 
Published: December 2023

AbstractBackgroundAlzheimer’s disease (AD) is the prevalent cause of dementia in older adults. Down Syndrome (DS) is the most common chromosomal disorder with strong predisposition to the development of AD. Cellular senescence contributes in the pathophysiology of both AD and DS but the mechanisms are unclear. Senescence associated secretory phenotype (SASP), which refers to a complex of secreted mediators, including soluble factors and extracellular vesicles (EVs) may contribute to the spread of senescence to bystander cells but its role in neurodegenerative disorders has not been evaluated.MethodParietal cortex tissue from patients with AD, DS, and normal/low‐pathology (NL) cases was obtained from the UC Irvine ADRC. The cryopreserved human tissue was used for small EV isolation by ultracentrifugation and size exclusive chromatography (SEC). Purity of the EV fractions was confirmed by immunoblotting against positive (CD63, CD9, Syntenin‐1) and negative (calnexin and GM130) EV/exosomal markers, transmission electron microscopy, and nanoparticle tracking analysis. Cell‐type specific EV fractions were isolated by immunoprecipitation (IP). Senescence transfer potential of brain‐derived EVs were assessed in neuroblastoma and glioma cells using senescence associate beta‐galactosidase activity assay, and confirmed by other senescence markers.ResultOur preliminary data demonstrated the ability of AD and DS, but not NL samples, to transfer senescence to neuroblastoma SH‐SY5Y and glioma U87‐MG cells. Senescence associate beta‐galactosidase activity was on average around 15% higher in cells treated with AD brain derived EVs (AD‐EVs) compared to NL brain EVs (NL‐EVs). This data correlates with around 20% elevation in p21 expression in AD‐EV treated cells. When senescence transfer potentials were compared between AD‐EVs and DS brain derived EVs (DS‐EVs), DS‐EVs exceeded AD‐EVs in their ability to transfer senescence‐like phenotype with around 40% increase in senescence associate beta‐galactosidase activity in cells treated with DS‐EVs. We are currently evaluating levels of senescence‐associated and SASP markers in AD and DS cells and cell‐type specific brain derived small EVs.ConclusionWe demonstrated an ability of AD and DS brain derived EVs to transfer senescence‐like phenotype in vitro. This phenomenon deserves further investigation to estimate its impact on the progression of AD in Down and non‐Down population along with evaluation its therapeutic potential.
Relationship between psychiatric symptoms and bidirectional change in subjective cognitive decline
Authors: Kann Michael , Chapman Silvia , Joyce Jillian L. , Waltrip Leah H. , Zeiger Peter , Rizer Sandra , Shagalow Shaina , Azar Martina , Cosentino Stephanie 
Published: December 2023

AbstractBackgroundSubjective Cognitive Decline (SCD) is increasingly recognized as a prodromal risk state for Alzheimer’s disease. However, relatively little is known about trajectories of SCD within cognitively normal older adults, or the factors that associate with SCD change in this group. In this study, we examine the extent to which specific psychiatric symptoms including anxiety, depression, and apathy associate with an individual’s change in SCD over time.MethodParticipants were community dwelling cognitively normal older adults. SCD was measured using a 20‐item age‐anchored questionnaire that assessed complaints of cognitive functioning. Anxiety, depression, and apathy were assessed using the Beck Anxiety Inventory(BAI), Geriatric Depression Scale(GDS), and Apathy Evaluation Scale(AES), respectively. Measurements were conducted at two timepoints (T1 and T2). Average duration between visits was 35.62 months(SD = 13.28). High SCD change individuals(HC), as opposed to low SCD change individuals(LC), were defined as those who’s total SCD rating changed more than ±1 SD from the mean change score. Regression models were conducted to examine the association between SCD change group and psychiatric symptoms.ResultParticipants were 82 cognitively normal older adults (6.1% Hispanic, 93.9% Non‐Hispanic; 79.3% White, 15.9% Black; 67% female; mean age = 70.96(SD = 6.98); mean education = 16.38(SD = 2.26)). 22 participants were classified as HC(11 with increasing SCD; 11 with decreasing SCD). Anxiety symptoms were higher in the HC group than the LC group at T1(6.57 vs 3.53, p = 0.013) and T2(6.70 vs 2.91, p = 0.003). After adjusting for demographics(age, gender, and education), only T1 anxiety was associated with the HC group(B = 0.297, p = 0.017).ConclusionIndividuals with greater change in SCD over time had higher levels of anxiety at baseline than individuals with relatively stable SCD. This was true for individuals who had a large increase in SCD as well as a large decrease. Our results inform the factors that may contribute to variability in SCD among cognitively normal older adults and underscore the importance of assessing anxiety along with SCD. Importantly, as psychiatric symptoms may also confer risk for future dementia, current findings do not undercut the potential relevance of SCD for future cognitive decline and dementia. Ongoing longitudinal research is examining the interplay of SCD change, psychiatric symptoms, objective cognition, and diagnostic conversion.