bluuebunny/crossref_metadata_2025_split huggingface dataset:
The role of glial cells in neuroinflammation in the context of Alzheimer’s disease
Authors: Lima Corrêa Ferreira Rafaella , Heimfarth Luana , Ferreira Sergio T. 
Published: December 2023

AbstractBackgroundAlzheimer’s disease (AD) is the world’s leading form of dementia. The pathogenesis of AD includes increased brain levels of β‐amyloid peptide oligomers (AβOs), neurotoxins associated with AD. The increase in oligomer concentration is neurotoxic and causes, among the damages, synapse loss, mitochondrial dysfunction and impairment of proteostasis mechanisms. Neuroinflammation, notably the activation of microglia and astrocytes to pro‐inflammatory states, has been associated with the pathogenesis of several neurodegenerative diseases. The current work aimed to evaluate the neuroprotective role of microglia in the context of the pathophysiology of AD.MethodThis study aims to investigate potential modulations in morphology and function of glial cells in experimental models of Alzheimer’s disease (AD), evaluating (1) the in vitro activation of microglia and astrocytes promoted by AβOs, and (2) in vivo microglia and/or astrocytic activation in mice receiving intracerebroventricular (icv) administration of AβOs. Expression of cytokines and glial markers were analyzed by RT PCR and Immunocytochemistry.ResultPreliminary results suggest an increase in glial activation markers, such as GFAP and F4/80, and complement immune system markers such as C1q, 7 days after icv infusion of AβOs. No significant differences were observed in the expression of TNF‐α. Immunocytochemical analyzes suggest greater nuclear factor‐KB translocation in microglial cells treated with AβOs compared to vehicle.ConclusionResults are consistent with an important role of glial cells in the pathogenesis of AD, with glial activity altered and activated in both in vitro and in vivo models. In the face of chronic processes, these cells can remain in an activated state, releasing cytokines, complement components and chemokines, which may contribute to the production and accumulation of Aβ and further exacerbate pathology.
Plasma metabolomic profiles of aged, humanized APOE mice and behavioral correlates
Authors: McLean John W. , Bhattrai Avnish , Simmons Hannah , Wiegand Jean‐Paul L. , Raikes Adam C. , Kaddurah‐Daouk Rima F. , Brinton Roberta Diaz 
Published: December 2023

AbstractBackgroundApolipoprotein E (APOE) plays a critical metabolic role by facilitating the binding of lipid complexes to cell surface receptors, providing tissues with energy substrates. The APOE‐ε4 (APOE4) polymorphism is the predominant genetic risk factor for late‐onset Alzheimer’s Disease (LOAD), while APOE3 is considered risk‐neutral. Female biological sex also nearly doubles LOAD risk. This study utilizes the JAX humanized APOE knock‐in mouse model to investigate the contributions of chromosomal sex and APOE genotype to plasma metabolic profiles, along with potential correlates to cognitive performance in a novel objection recognition (NOR) task.MethodMale and female mice aged 23‐25 months old (37M/32F) with humanized APOE3/3, APOE3/4, and APOE4/4 genotypes underwent blood plasma extraction and subsequent metabolic profiling via mass spectrometry using the Biocrates MxP® Quant 500 platform. A subset of animals (34M/28F) additionally performed an NOR paradigm prior to metabolic profiling. Two‐way ANOVA and post‐hoc t‐tests were utilized to determine data significance.ResultMetabolomic analyses indicated that male mice exhibited relatively higher levels of glucogenic amino acids, including glycine, asparagine, and histidine. In contrast, female mice had higher levels of TMAO and ADMA along with lower levels of phosphatidylcholines, cholesteryl esters (CE), and triglycerides. In males, APOE3/4 and APOE4/4 genotypes were associated with lowered CE levels. APOE3/4 female mice had the lowest CE plasma concentrations. Female APOE4/4 mice had increased concentrations of several diglyceride and triglyceride species, relative to APOE3/3 and APOE3/4 female mice. Behavioral correlates indicated that triglyceride levels negatively correlated with locomotion throughout the NOR paradigm. Memory performance, as determined by the discrimination index, positively correlated with plasma concentrations of glycine and negatively correlated with hydroxy acylcarnitine levels.ConclusionIn mice aged to resemble a ∼70‐year‐old human population, these results suggest that biological sex affects peripheral metabolic profiles greater than APOE genotype. Male metabolism was characterized by elevated glucogenic amino acid levels; female metabolic profiles demonstrated increased TMAO and lower phosphatidylcholines and triglycerides, suggesting differences in lipid metabolism. APOE3/4 genotype was associated with lowered CE in both sexes while APOE4/4 females had higher triglycerides, indicating potential sex‐genotype interactions upon metabolism that may confer elevated LOAD risk and influence behavior.
Salivary lactoferrin for detection of early stage Alzheimer’s disease
Authors: Bunprakop Saowalak 
Published: December 2023

AbstractBackgroundAs the global population ages, the incidence of dementia is projected to increase significantly in the coming years, with Alzheimer’s disease (AD) being the leading cause. To address this impending public health crisis, there is a critical need to identify simple and reliable biomarkers for early AD diagnosis. While current diagnostic approaches include cerebrospinal fluid analysis and positron emission tomography (PET), they are often unavailable in resource limited settings. Recent research has highlighted the potential utility of salivary lactoferrin (Lf) as a promising biomarker for AD diagnosis. In this study, we aim to assess salivary Lf levels in early‐stage AD patients in comparison to non‐demented elderly controls, with the goal of further elucidating the diagnostic utility of this biomarker.MethodA total of 81 saliva samples were collected from 28 early‐stage AD patients and 53 nondemented elderly controls. The diagnosis of AD was made clinically using the current guidelines (Jack et al., 2018; Dubois et al., 2021) and 70.4% of participants underwent biomarker testing using amyloid‐PET or plasma phosphorylated tau181 (p‐tau181). Salivary Lf levels were compared between the two groups and the diagnostic performance of Lf was evaluated in these early‐stage patients.ResultAmong 81 participants included, 53 (65.4%) were female. The median age was 69 years (interquartile range: 62.8‐76.0). Salivary Lf levels decreased significantly among early‐stage AD patients compared to controls (median: 5.03 vs 26.85, P<0.01). Salivary Lf showed strong correlation with plasma p‐tau181 (Spearman Rho = ‐0.51, P<0.01) but not with age (Spearman Rho = ‐0.17, P = 0.15). For diagnosing AD in early‐stage patients, salivary Lf levels demonstrated an area under the curve of 0.93 (95% confidence interval 0.82‐0.98).ConclusionConsistent with prior findings, diagnostic performance of salivary Lf is substantial. Further research endeavors should conduct a comprehensive assessment of this biomarker against a robust, biomarker‐based reference diagnosis. If validated, the ease of saliva collection could potentially make it an attractive option for population‐wide screening and early identification of undiagnosed individuals with AD in its early stages.
Abnormalities in Occipital Cortical Sources of Resting‐State EEG Rhythms in Patients with Epileptiform Activity and Mild Cognitive Impairment due to Alzheimer’s Disease
Authors: Salamone Enrico Michele , Noce Giuseppe , Tucci Federico , Jakhar Dharmendra , Lopez Susanna , Lizio Roberta , Percio Claudio Del , Babiloni Claudio 
Published: December 2023

AbstractBackgroundAlzheimer’s Disease (AD) patients present a higher risk of developing epilepsy compared to the age‐matched general population. Neurodegenerative cognitive disorders in general are closely linked with epilepsy and subclinical Epileptiform Electroencephalographic Activity (EEA). Furthermore, AD with Mild Cognitive Impairment (MCI) patients present abnormalities in posterior cortical sources of resting‐state eyes‐closed EEG rhythms at delta (< 4 Hz) and low‐frequency alpha (8‐10 Hz) rhythms. This retrospective study tested the hypothesis that ADMCI patients with EEA (ADMCI‐EEA) may be characterized by specific disease‐related abnormalities in delta and alpha rsEEG source activities compared with ADMCI patients without EEA (ADMCI‐noEEA) and noADMCI controls.MethodWe analysed data from an international database (www.pdwaves.org) comprising clinical, neuropsychological, rsEEG (25‐30 minutes), cerebrospinal fluid (CSF), and structural magnetic resonance imaging (sMRI) data in n = 42 ADMCI and n = 32 noADMCI patients without a diagnosis of epilepsy. The database also included clinical, neuropsychological, and rsEEG data of n = 38 matched cognitively unimpaired elderly (Nold) persons, used as additional controls in the present study. The rsEEG traces were reviewed by expert epileptologists blinded to the diagnostic status. EEA was detected in n = 8 ADMCI and n = 13 no‐ADMCI patients (Table 1). Individual alpha frequency peak (IAF) was used to determine the rsEEG delta, theta, and alpha bands. Regional rsEEG cortical sources were estimated using the eLORETA freeware.ResultCompared to the Nold and noADMCI‐noEEA groups, the noADMCI‐EEA group showed greater temporal rsEEG delta cortical source activity. Conversely, compared to the Nold and ADMCI‐noEEA groups, the ADMCI‐EEA group showed greater temporal and occipital rsEEG delta cortical source activity (Figure 1). Notably, CSF amyloid (but not sMRI‐based cortical atrophy) burden was greater in the ADMCI‐EEA than in ADMCI‐noEEA patients (Table 2).ConclusionThe abnormal temporal rsEEG delta cortical source activity in the ADMCI‐EEA and noADMCI‐EEA groups may reflect an unspecific susceptibility of the temporal lobe to slowing rsEEG activity for several neuropathological processes. Instead, the abnormal occipital rsEEG delta cortical source activity in the ADMCI‐EEA over the control groups may reflect a specific susceptibility of the occipital lobe to slowing rsEEG activity for AD‐related neuropathological processes in the cholinergic tract to the occipital cortex.
Signalling pathways associated with impaired angiogenesis in Alzheimer’s Disease
Authors: Tsartsalis Stergios , Sleven Hannah , Fancy Nurun N , Wessely Frank , Willumsen Nanet , Michal Rokicki , Chau Vicky , Ifie Eseoghene , Khozoie Combiz , Ansorge Olaf , Owen David R , Webber Caleb , Jackson Johanna , Cader Zameel , Matthews Paul M 
Published: December 2023

AbstractBackgroundBrain perfusion and blood brain barrier (BBB) integrity are reduced in Alzheimer’s disease (AD). We hypothesized that b‐amyloid (Aβ) induces dysfunction of pathways in vascular cells that regulate angiogenesis.MethodWe performed single nucleus RNA sequencing (snRNAseq) of vascular cells isolated from post mortem samples from multiple cortical regions from AD patients (Braak V‐VI) and non‐diseased controls (NDC, Braak 0‐II). We developed a meta‐analytic approach to integrate these data with related publicly available datasets. We performed differential gene expression (DGE) analyses as a categorical comparison of AD vs NDC and as a confound‐controlled regression of transcriptomic alterations by regional total Aβ. We also performed cell‐specific gene co‐expression analyses identify modules differentially expressed in AD relative to NDC.ResultOur results describe differential expression of genes central to pathways sustaining angiogenesis, proliferation and migration of endothelial cells and the integrity of the BBB with either AD or greater pathological protein load. HIF1A and FGF2, proangiogenic molecules which both induce VEGF, are upregulated in EC, consistent the parenchymal hypoxic response shown repeatedly in prior studies. However, components of signalling pathways downstream of VEGFR2 are downregulated, suggesting a pathological block to angiogenesis with greater Aβ load. While the proangiogenic stimuli promote the expression of genes such as PPP3CA and ITPR1, coding for calcineurin, which contribute to VEGF signalling through the PLCγ‐Ca2+ signalling pathway are upregulated in AD, expression of RAC1 and RHOJ, which enable cellular migration and adhesion, is downregulated. While ANGPT2 expression is also upregulated, the angiopoietin receptor (TIE2, coded by TEK) is downregulated. Downregulation of ADAM10 in AD and upregulation of other NOTCH pathway genes with greater Aβ load suggests altered NOTCH signalling.ConclusionOverall, a hypoxic tissue environment in AD is accompanied by dysfunctional angiogenesis related to Aβ load. Evidence for multiple sites of dysfunction were identified, involving impaired angiopoietin responses, vascular cell migration and NOTCH signaling.
A study on the sample representativeness of the Wisconsin Alzheimer’s Disease Research Center Clinical Core participants versus the Wisconsin state population
Authors: Ma Yue , Pinzon Maria C Mora , Buckingham William R. , Bersch Andrew , Powell W. Ryan , LeCaire Tamara J. , Ennis Gilda E. , Deming Yuetiva , Jonaitis Erin M. , Reuter Leah , Shi Fangfang , Spalitta Alice , Wahoske Michelle L , Bevis William B. , Blazel Hanna M. , Chin Nathaniel A. , Edwards Dorothy F. , Walaszek Art , Okonkwo Ozioma , Chappell Richard J , Johnson Sterling C , Asthana Sanjay , Gleason Carey E. , Kind Amy J. , Bendlin Barbara B , Carlsson Cynthia M 
Published: December 2023

AbstractBackgroundUnderstanding how representative a research sample is compared to the population can help inform future recruitment planning, data analysis strategies, and interpretation of the generalizability of the findings. We compared the demographics, rural residence, neighborhood socioeconomic disadvantage, and vascular risk factors between the Wisconsin Alzheimer’s Disease Research Center (ADRC) Clinical Core participants versus the Wisconsin state adult population.MethodThe ADRC participant sample (n = 678) included all active participants as of November 30, 2021. The state population statistics were estimated using multiple national and state data sources. Differences between the sample versus the population were tested using the one‐sample z‐test, the one‐sample Wilcoxon signed rank test, the exact binomial test, and the exact Monte Carlo multinomial test. Except for age, comparisons were performed for two age groups: 45‐64 years and ≥ 65 years, separately.ResultThe ADRC participants are older than the state population. For each age group, compared to the state population, the ADRC participants include more women and greater proportions of Black and American Indians, have higher levels of educational attainment, have smaller percentages living in rural areas and more disadvantaged neighborhoods, and show lower vascular risks. The sample versus population differences are greater for the ≥ 65 years group (the group at higher risk for AD) than the 45‐64 years group for most metrics, however, are smaller for sex and neighborhood disadvantage.ConclusionThe ADRC targets recruiting middle‐aged and older adults with dementia, mild cognitive impairment, or increased risk for AD. Thus, the participants are not a suitable sample for epidemiology studies on AD prevalence. Oversampling underrepresented racial groups would alleviate the lack of statistical power associated with small or unbalanced sample sizes and increase the precision in effect size estimates for studies on racial disparities. Future recruitment should endeavor to include participants from a broader range of educational backgrounds and more residents in rural areas and disadvantaged neighborhoods. These subpopulations have inequitable access to quality health care and are at greater risk. Properly representing them in research would allow conclusions to be generalizable to these subpopulations and support policy making to meet their needs.
Assessing the functional effect of the Presenilin‐1 G206A variant on age of onset of Alzheimer Disease in the Puerto Rican population
Authors: Celis Katrina , Rajabli Farid , Griswold Anthony J. , Adams Larry D. , Tejada Sergio J. , Sanchez Jose Javier , Simon Shaina A. , Hamilton‐Nelson Kara L. , Gomez Nicholas R , Whitehead Patrice , Mena Pedro R. , Arvizu Jamie , Golightly Charles G. , Silva Concepcion , Acosta Heriberto , Cuccaro Michael L. , Vance Jeffery M. , Beecham Gary W. , Feliciano‐Astacio Briseida E. , Dykxhoorn Derek M. , Young Juan I. , Pericak‐Vance Margaret A. 
Published: December 2023

AbstractBackgroundThe variant G206A in Presenilin‐1 (PSEN1) gene has been identified almost exclusively in Alzheimer Disease (AD) Puerto Rican families. This variant represents a founder effect on the African background. The G206A variant associates with extreme variability in age of onset (AOO), ranging from 30 to 90 years. In contrast, other variants at the same amino acid of PSEN1 (G206N, G206S) have a tighter range of AOO (30‐35 years). We aim to identify the molecular mechanisms involved in the AOO variability between G206A carriers through functional analysis of induced pluripotent stem cells (iPSCs).MethodGenotyping data were phased using SHAPEIT to identify local ancestry and RFMix to estimate genetic ancestry. p‐Tau181 levels were tested from plasma using Simoa (Quanterix HD‐X). iPSCs of G206A carriers with different AOO were reprogrammed using non‐integrating Sendai virus. These clonal lines were assessed for pluripotency and chromosomal stability Isogenic construction of G206A iPSC lines is currently in progress.ResultWe screened for G206A carriers using whole genome from 896 individuals (182 families) and identified 43 carriers (39 AD and 4 cognitively unimpaired <65 years) from 8 families and 3 isolated cases. 55% of AD G206A carriers had AOO <65. A single African haplotype was identified in all G206Acarriers. We observed higher pTau181 levels in AD G206A carriers with early age of onset, compared to those with late onset. Association analysis did not identify APOE4 or SYNJ1 polymorphisms as contributing to the differences in AOO within G206A carriers. To perform functional studies, we selected three with early (<65) and three with late (>65) AOO AD peripheral blood mononuclear cells (PBMCs)that were reprogrammed into iPSC lines. G‐band Karyotype, factor loss analyses, genetic finger printing, immunocytochemistry (ICC) and qRT‐PCR for intracellular and surface pluripotency markers was confirmed in the iPSC lines.ConclusionThe PSEN1 G206A variant, originating in African ancestry haplotype revealing a founder effect, is an important contributor to AD in an underserved population. Understanding the role of the G206A variant in AD pathogenesis and the factors that influence its effect on AOO will provide insight on AD pathogenesis, age of onset variation and identification of potential novel therapeutic targets.
Rare cause of dementia in childhood
Authors: Dubey Shubham , Dubey Ayush 
Published: December 2023

AbstractBackgroundDementia is rare in paediatric age group. While inborn errors of metabolism account for majority of the causes, structural abnormalities are also responsible for cognitive decline in few patients. We present such a rare case here.MethodAn eight year old female presented to Neurology department with complaints of decline in memory, poor judgement and social disinhibition since two months with three episodes of focal with impaired awareness seizures. On examination, she had MMSE score of 8/30 and no motor weakness or abnormal reflexes. She was evaluated for her symptoms.ResultMRI showed elongated curvilinear altered signal intensity structure consistent with fat at inter‐hemispheric fissure, pericallosal in location, adjacent to body, isthmus and splenium of corpus callosum indicating pericallosal lipoma (curvilinear type).ConclusionPericallosal lipoma is a rare congenital malformation of brain that can be associated with dysgenesis or agenesis of the corpus callosum. It is usually asymptomatic, but can manifest with seizures, dementia, paralysis or headaches. CT and MR imaging play an important role in making this diagnosis.
Multimodal music therapy intervention for engagement and agitation reduction for persons with severe dementia: Study protocol of a pilot randomized cross‐over trial
Authors: Reschke‐Hernandez Alaine E. , Ross Meghan , Davis Hayley Rene , Latham Emma Foret , Veblen Nora Bryant 
Published: December 2023

AbstractBackgroundMusic‐based interventions may support the well‐being of persons with dementia (PWD). However, limited empirical evidence exists regarding the optimal use of such interventions for specific outcomes and at different disease stages. Project goals are to 1) demonstrate proof‐of‐concept and feasibility of a music therapy intervention for care facility residents with severe dementia and 2) obtain preliminary data. Here, we describe the study protocol.MethodThe multimodal intervention, led by a music therapist, uses live participant‐preferred music and progressively layers singing and rhythmic instrument playing concurrent with participant behavioral responses. It is grounded in the “Clinical Practice Model for PWD,” a person‐centered framework that presents a schema regarding why particular care strategies are important and how to implement them (Reschke‐Hernández, 2019; 2021). This randomized cross‐over design has 4 blocks: Baseline, 3‐week treatment period, 1‐week washout (no intervention), and 3‐week treatment period. The comparison treatment consists of short stories read aloud, using the same non‐music strategies, small group format (3‐5 people per group), and dosage (2x/week for 30 minutes) as the combined music interventions. Outcomes include ratings of engagement (primary outcome), agitation, and arousal. To evaluate our study design within the care milieu, we will perform semi‐structured interviews with up to 10 caregivers at participating facilities. The Menorah Park Engagement Scale (Camp et al., 2015) and Observed Emotion Rating Scale (OERS; Lawton et al., 1999) are used to measure engagement and agitation, and the Neuropsychiatric Inventory‐Nursing Home (Wood et al., 2000) to measure agitation and occupational disruptiveness. The OERS, data on functional transfers, pulse oximetry, and a wearable activity tracker (including sleep data) are used to measure arousal.ResultsPlanned enrollment is 20 PWD. Recruitment will occur in partnership with care facilities from January to May 2023, with active data collection beginning in February. Preliminary data will be available in March with results in July 2023.ConclusionProgressive layering of musical stimuli coupled with purposeful activity, matched to participants’ cognitive capacity, may promote purposeful engagement, thereby supporting arousal regulation and reducing agitation. A key deliverable will be enhanced practical understanding of how to measure effectiveness of music‐based interventions for PWD.