bluuebunny/crossref_metadata_2025_split huggingface dataset:
Can MBI‐C scores predict time‐to‐cognitive worsening in CU, SCD, and MCI participants? Evidence from the CompAS study
Authors: Mallo Sabela Carme , Juncos‐Rabadán Onésimo , Lojo‐Seoane Cristina , Pérez‐Blanco Lucía , Felpete Alba , Moreno‐Carretero M. José , Rojo‐Pantoja Águeda , Nieto‐Vieites Ana , Rozas Arturo X. Pereiro 
Published: January 2025

AbstractBackgroundThe role of neuropsychiatric symptoms (NPS) as early markers of cognitive impairment progression along the cognitive impairment continuum needs further research. Our objective was to estimate to which extent NPS, measured with the Mild Behavioral Impairment Checklist (MBI‐C), predict time‐to‐cognitive‐worsening during follow‐up in a sample of older adults recruited from primary care centers while controlling for other related variables (i.e., age, gender, years of education, comorbidity, and cognitive complaints).MethodA multivariate Cox proportional hazard regression model was performed using the ‘Enter method’. Two hundred twenty‐six participants from the Compostela Aging Study (CompAS) were included in the analyses (none censored). Participants were diagnosed at baseline as Cognitively Unimpaired (CU = 144), Subjective Cognitive Decline (SCD = 37), and Mild Cognitive Impairment (MCI = 45) (Table 1). The event was defined as stability or worsening in cognitive status over a follow‐up of 17‐75 months, during which three evaluations were performed. Stability was considered when the diagnosis remained stable and worsening when progression to MCI or dementia occurred. The groups at baseline (CU, SCD, MCI) were entered into the model as strata. MBI‐C total score at baseline was introduced as a covariate and adjusted by age, gender, years of education, comorbidity, and SCCs from participants and informants.ResultsThe tested model was statistically significant [overall significance: ‐2 Log Likelihood = 1620.73, χ2
= 17.63, df = 7, p < .014]. MBI‐C total score was the only significant variable [β = .038, SE = .014, Wald = 7.77, p < .005]. Its corresponding hazard ratio was 1.039 (95% CI 1.011‐1.068), indicating that for one unit increase in the MBI‐C total score, the risk of worsening increases by 1.039 for a month (Table 2).Figure 1 shows the survival function using covariates for each group. The greatest differences were observed in the time interval 20‐60 months, and especially between the MCI and CU. SCD curve remained stable during that period and was more similar to the MCI curve.ConclusionOur results indicated that MBI‐C can significantly predict time to worsening along the cognitive impairment continuum. Further, differences between MCI and CU participants' trajectories were especially pronounced around 40‐60 months, with SCD falling between the two groups.
Apolipoprotein E4 contributes to Alzheimer’s disease neuropathology in Down syndrome
Authors: Dooling Breanna , Summers Rose , Quang Daphne , Joshi Molishree , Esquer Hector , Potter Huntington , Johnson Noah R 
Published: January 2025

AbstractBackgroundAdults with Down syndrome (DS) develop Alzheimer’s disease (AD) brain pathology by their 40s due to triplication of the amyloid precursor protein (APP) gene on chromosome 21, and most develop clinical symptoms by age 50‐60. Inheritance of the apolipoprotein E (apoE) ε4 allele (APOE4) is the strongest risk factor for AD besides age, whereas the ε3 allele (APOE3) does not change AD risk. The APOE4 genotype is associated with earlier and more rapid cognitive decline in both typical AD and DS‐associated AD (DS‐AD); however, understanding of the associated mechanisms is lacking.MethodWe developed cerebral organoids (COs) from trisomy 21 (T21) and disomy 21 (D21) APOE3/3 human induced pluripotent stem cell (hiPSC) lines. We then used CRISPR‐Cas9 editing to modify our hiPSCs from an APOE3/3 genotype to APOE4/4 in DS hiPSCs and in matched control hiPSCs disomic for chromosome 21. We differentiated these hiPSCs into COs as well as into monolayer cultures of astrocytes and microglia.ResultThere was a significant decrease in size from D21 COs to T21 COs. T21 COs also accumulated more apoE and Aβ than D21 COs and at earlier timepoints. T21 and APOE4/4 each resulted in increased microglial size and decreased microglial roundness. T21 astrocytes accumulated more apoE than D21 astrocytes. T21 APOE4/4 astrocytes exhibited increased cell death compared to T21 APOE3/3 astrocytes at an early timepoint.ConclusionAPOE4/4 further accelerates and enhances AD neuropathologies in people with DS. Understanding the molecular and cell type‐specific changes caused by APOE4 as compared to APOE3 in DS‐AD will aid in the development of more targeted and proactive therapies to alleviate dementia risk in individuals with DS.
Local ancestry in Apoe3: Friend or Foe?
Authors: Moura Sofia , Celis Katrina , Nasciben Luciana Bertholim , Rajabli Farid , Rivero Joe , Hamilton‐Nelson Kara L. , Whitehead Patrice L. , Gearing Marla , Bennett David A. , Flanagan Margaret E , Weintraub Sandra , Geula Changiz , Scott William K. , Davis David A. , Vontell Regina T , Schuck Theresa , Dykxhoorn Derek M. , Pericak‐Vance Margaret A. , Griswold Anthony J. , Young Juan I , Vance Jeffery M. 
Published: January 2025

AbstractBackgroundNon‐Hispanic White APOE4 carriers have a higher risk of developing AD compared to African American APOE4 carriers. The local ancestry (LA) surrounding the APOE region was previously shown to be the primary factor in this risk difference. APOE4 carriers of European LA (ELA) have been found to have higher APOE4 expression and chromatin accessibility compared to African LA (ALA). We sought to investigate whether the LA around APOE3 has the same effect between ancestries. Differences between alleles could provide insight into ancestry‐specific regulatory areas controlling the APOE4 expression.MethodWe identified AD autopsy samples by GSA, all homozygous for APOE3 and LA from 4 ADRC brain banks: Miami, Emory, Duke, and Rush. We performed single nuclei RNA sequencing (snRNA‐seq) on eight frozen frontal cortex (B9 area) samples using 10x Genomics.ResultWe performed snRNA‐seq in a total of 51,462 nuclei from eight brains (4 ELA and 4 ALA). We identified 35 distinct cell clusters at a resolution of 0.6. The proportion of cells per cluster between ELA and ALA samples was similar for all clusters, except for cluster 32 (Excitatory Neurons) which had a greater than 2‐fold difference in ALA. Our data shows that APOE3 carriers with ELA have a significantly higher APOE expression in Excitatory Neurons (cluster 7) than those of ALA and contrary to our previous observations in APOE4 carriers (Griswold, A. et al, (2021)), APOE3 carriers of ALA express higher APOE in astrocytes (cluster 2) and Microglia (cluster 6). However, overall, comparison of APOE3 vs APOE4 carriers in this study demonstrated that APOE3 alleles have significantly lower gene expression than APOE4 carriers of the same LA.ConclusionOur preliminary data suggest that the LA surrounding APOE3 is associated with different effects on APOE expression compared to APOE4 allele. Further, within the same LA, we observed that, overall, the different cell types express less APOE in APOE3 carriers compared to APOE4 carriers. Altogether, this may provide additional insight into the regulatory mechanisms affecting APOE4 expression.
Association of grip strength and gait speed with structural brain volume in older adults with and without cognitive impairment.
Authors: Cole Keith R , Full Kelsie M , Shi Hui , Pechman Kimberly R. , Shashikumar Niranjana , Davis L. Taylor , Hohman Timothy J. , Jefferson Angela L. 
Published: January 2025

AbstractBackgroundGrowing evidence supports that measures of overall physical health are related to incidence and progression of Alzheimer’s disease and related dementias (ADRD). In particular, measures of gait speed and grip strength independently predict incident dementia and cognitive decline in older individuals. Less is known regarding their relationship with structural brain volume in the presence of cognitive impairment. This study examined the relationship between gait speed and grip strength, and regional brain volumes in older adults with and without cognitive impairment.MethodsParticipants included 570 adults (59% males; n = 412 cognitively unimpaired; n = 158 mild cognitive impairment) aged 50‐92 years (M = 69.0, SD = 9.0) from the Vanderbilt Memory and Aging Project. Participants underwent 3T brain magnetic resonance imaging (MRI) at study enrollment. Cross‐sectional multivariate linear regression models were used to determine the associations between gait speed (usual walking pace over 15 ft) and grip strength (greatest of three maximum effort trials) with hippocampus and frontal, temporal, parietal, and occipital lobe volumes. Covariates included age, biological sex, ethnicity, education, BMI, global depression scale, Framingham Stroke Risk Profile, APOE ε4 status, cognitive status, and intracranial volume. The model included interaction terms of gait speed and grip strength each with biological sex and cognitive status.ResultsIn fully adjusted models, poorer grip strength was only associated with lower hippocampal volume (F(13,491) = 26.3, R2adjusted = 0.4, p = 0.001). Sex interacted with grip strength (p = 0.03) on hippocampal volume such that the association was present among male (p = 0.006) but not female participants (p = 0.46). Slower gait speed was only associated smaller frontal lobe volume (F(12,488) = 51.0, R2adjusted = 0.56, p = 0.04) without interaction with sex (p = 0.95). There was no evidence of interaction with cognitive status in any model (all p’s>0.05).ConclusionGrip strength and gait speed, both quick and easy clinical measures, are differentially related to structural brain volume. Grip strength is related to hippocampal volume only in male older adults with and without cognitive impairment, indicating potential influence of biological sex. Gait speed, however, is related to frontal lobe volume in both males and females. Changes in distinct measures of physical health of those with and without cognitive impairment may indicate changes in different regions of the brain.
Procedural practice effects in remote digital memory assessment
Authors: Basche Kristin E , Berron David , Peterson Amanda , Rosario Hannah , Johnson Sterling C. , Düzel Emrah , Clark Lindsay R. 
Published: January 2025

AbstractBackgroundFrequent and remote cognitive assessment may improve sensitivity to subtle cognitive decline associated with preclinical Alzheimer’s disease (AD). However, repeated testing can result in unintended inflation of scores, due to practice effects. The objective of this study is to evaluate the extent of sessions with non‐identical stimuli on performance and determine if study design or amyloid PET status moderates the impact of practice.MethodParticipants were recruited from longitudinal aging cohorts to complete medial temporal lobe‐based memory paradigms (Object‐In‐Room Recall [ORR], Mnemonic Discrimination for Objects and Scenes [MDT‐OS 1‐back and 2‐back], Complex Scene Recognition [CSR]) using the neotiv application at repeated intervals over one year. Participants were randomized to a task schedule (biweekly 1 task or bimonthly burst) for a total of 24 ten‐minute remote sessions. In both groups, participants completed each task 6 times; the interval between identical tasks was eight weeks (Table 1). Linear mixed effects models were used to assess the impact of practice on task performance and the interaction of practice with (1) task schedule group or (2) amyloid status. Models contained person‐level random intercepts and covariates of age, gender, education, and device type (tablet or smartphone).ResultsTask schedule group did not differ by demographic characteristics (Table 2, n = 133, mean age = 68.2, 67% female, 87% white, 97% cognitively unimpaired). The interaction of practice x task schedule group was only significant for the MDT‐OS (Table 3, β = 0.01, p = 0.032). The main effect of practice was significant for the ORR (β = 0.20, p = 0.002) and CSR (β = 0.001, p<0.001) tasks. The interaction of practice x amyloid PET result was not significant in any models. The main effect of practice was significant in all models (Table 3, ORR: β = 0.21, p = 0.004; CSR: β = 0.01, p<0.001; MDT‐OS: β = 0.01, p = 0.034).ConclusionPractice effects were present, indicating that procedural practice benefited task scores, despite non‐repeating stimuli. The MDT‐OS group x practice interaction indicated that participants in the burst design group had lower scores at their initial MDT‐OS visit, but increased performance with practice at a higher rate. No main effects or interaction of amyloid result was observed, possibly due to limited availability of data and few elevated participants.
The cellular prion protein mediates Tau oligomer‐induced memory impairment in mice
Authors: Forloni Gianluigi , Balducci Claudia , Orsini Franca , Cerovic Milica , Masone Antonio , Raimondi Ilaria , Lavigna Giada , Zucchelli Chiara , Beeg Marten , Colombo Laura , Musco Giovanna , Gobbi Marco , Chiesa Roberto , Fioriti Luana 
Published: January 2025

AbstractBackgroundThe role of oligomeric forms of various proteins as direct responsible of neuronal dysfunction in neurodegenerative disorders has been supported by numerous findings at experimental level and, more recently, by histological examinations in human material. The cellular prion protein (PrPC) has been proposed to mediate the neurotoxicity of β‐amyloid, α‐synuclein and tau oligomers. We demonstrated that although amyloid‐β oligomers (AβOs) bind with high affinity to PrPC, the memory deficit induced by intracerebroventricular (ICV) administration of AβOs in mice was not mediated by PrPC. Moreover, we did not confirm the reported interaction between α‐synuclein oligomers and PrPC, and found that their effect on memory did not depend on PrPC expression. In this study, we examined the interactions between tau oligomers (TauOs) and PrPC by chemico‐physical and functional studies.MethodTauOs were prepared in the presence of arachidonic acid and analyzed by atomic force microscopy; the interaction between TauOs and PrPC was investigated by surface plasmon resonance (SPR); the cellular localization of TauOs was studied in HEK293 cells expressing different levels of PrPC; the effect of TauOs on memory function was assessed by the novel object recognition test (NORT) after ICV injection (1µM 7.5 µl) in wild type (wt) and PrP knockout (KO) mice; the effect of TauOs on long‐term potentiation (LTP) was analyzed in hippocampal slices.ResultSPR demonstrated a high‐affinity binding between TauOs and PrPC with a Kd in the range of 20‐50 nM. Immunofluoresce analysis showed a PrPC dose‐dependent association of TauOs with the plasma membrane of HEK293 cells, and their co‐localization with PrPC. ICV application of TauOs induced memory impairment in wt but not in PrP KO mice. Accordingly, TauOs inhibited hippocampal LTP in a PrPC‐dependent fashion.ConclusionIn contrast to our previous findings with Aβ and α‐synuclein oligomers, we demonstrate that PrPC interacts with TauOs and this binding has functional consequences. This interaction might represent an interesting therapeutic target in Alzheimer’s disease and other tauopathies.
Cognitive Domains and Functional Assessment Questionnaire (CDFAQ): Accuracy Across Educational Levels
Authors: Maia Isabelle de Aguiar , Tavares Caio Peixoto , Moro Giovanna Correia Pereira , de Souza Aline Siqueira , Ferreira Jéssica Diniz , Burgos Ivonne Carolina Bolaños , Engelmann Gabriela Tomé Oliveira , Diniz Maissa Ferreira , Romano‐Silva Marco Aurélio , de Paula Jonas Jardim , Bicalho Maria Aparecida Camargos , Viana Bernardo de Mattos 
Published: January 2025

AbstractBackgroundThe Cognitive Domains and Functional Assessment Questionnaire (CDFAQ) assess cognitive and functional decline for Neurocognitive Disorders based on the DSM‐5 criteria (1). It’s accuracy to the Informant Questionnaire on Cognitive Decline in the Elderly ‐ Long Version (IQCODE‐LV) has been assessed (2), and was translated and validated into English. The informant version (CDFAQ‐IV) assess: Complex Attention (CA), Executive Functions (EF), Learning and Memory (LM), Language (L), Perceptual‐Motor (PM) and Social Cognition.MethodsTo evaluate the CDFAQ‐IV’s accuracy to IQCODE‐LV across participant’s educational levels. Both questionnaires were applied to 196 informants of older adults. Older adults were stratified by educational levels into three groups: 73 participants had low educational level (0‐3 years), 71 had middle educational level (4‐7 years), and 52 with high educational level (8 or more years). Accuracy assessment was made by Receiver Operating Characteristic (ROC) and cut‐off values defined by Youden’s J statistic. This study was approved by the ethics committee of UFMG.ResultsThe low educational group had good accuracy (Area Under the Curve = 0.879) for the CDFAQ‐IV total score, excellent accuracy for the EF domain (AUC = 0.907), good accuracy for LM domain (AUC = 0.822) and poor accuracies for other domains. For the middle educational group, CDFAQ‐IV (AUC = 0.908) and LM domain (AUC = 0.914) showed excellent accuracies, while CA (AUC = 0.876), L (AUC = 0.832) and SC (AUC = 0.814) domains showed good accuracies. The others domains showed poor accuracies. For high educational group, LM domain (0.924) had excellent accuracy, while CDFAQ’s total score (AUC = 0.894) and L domain (AUC = 0.898) showed good accuracy. Poor accuracies were found for the other domains.ConclusionsCDFAQ’s total score shows good accuracy in samples of low and high educational levels and excellent accuracy in samples with 4 to 7 years of schooling. Interestingly, the LM domain shows excellent accuracy (AUC > 0.9) in samples with higher levels of education. Brazilian older adults have lower educational levels and more heterogeneity in schooling quality compared to those from high‐income nations. Assessment of psychometric properties according to education is needed, as well as more scenarios such as studies in community and clinical settings.
Analysis of the production in a connected speech task in patients with language impairment
Authors: Redondo Santiago , Paolantonio Patricia , Romanelli Sofía , Andreotti Daniela , Matar Lourdes , Vita Luciana , Vivas Leticia 
Published: January 2025

AbstractBackgroundNeuropsychological language assessment batteries usually include connected speech tasks (e.g. the description of a picture). These tasks are assessed using different indicators that cover various levels of language: phonetic and phonological, lexico‐semantic, syntactic and discourse. Objective: to analyze linguistic and acoustic indicators for the picture description task of the Minlinguistic State Examination (MLSE) in its Argentinean version.MethodThe sample included 22 patients with aphasia due to focal and degenerative etiologies (10 APP, 1 DCB, 11 post‐stroke aphasia) classified into three clinical profiles: fluent, anomic and non‐fluent (according to Grossman, 2018) and 23 healthy participants. The task consisted of an oral description of the MLSE picture for 1 minute and it was audio recorded. Acoustic indicators were analyzed using the Praat software.ResultRegarding acoustic indicators, significant differences were observed in the duration of pauses between the three clinical groups and the control group, while the differences in vocalization and silence segments were significant between the non‐fluent and the control group. Regarding linguistic indicators, a significant difference was observed between the clinical and control groups in the number of nouns, words/time ratio, number of semantic units, the density of semantic units, speaking average, and number of complete utterances; while significant differences were observed between the control group and the non‐fluent and anomic groups in number of adverbs, non‐noun words, closed words, number of verbs, average number of nouns, utterances higher and lower number of words, mean length of utterance, and utterance rate. Besides, significant differences were observed between the fluent aphasia and the control groups in semantic errors and density of ideas; and between the no fluent aphasia and the control groups in number of total utterances and index of discourse. Among the clinical groups, significant differences were observed between the non‐fluent and fluent groups in the number of semantic errors; and between the anomic and non‐fluent groups in the noun/number of words relationship.ConclusionThese results illustrate how the use of linguistic and acoustic indicators in a connected speech task can provide additional information to identify the type of difficulties presented by aphasia patients.
Examining APOE4 overexpression effects in iAstrocytes across European and African ancestries
Authors: Dykxhoorn Derek M. , Oron Oded , Trittipo Jack , Adams Larry D. , Starks Takiyah D. , Acosta Heriberto , Feliciano‐Astacio Briseida E. , Byrd Goldie S. , Pericak‐Vance Margaret A , Griswold Anthony J. , Vance Jeffery M. , Young Juan I 
Published: January 2025

AbstractBackgroundThe Apoliproprotein E (APOE) e4 allele is the most significant genetic risk factor for late‐onset Alzheimer disease (AD). However, the risk associated with the APOE e4 allele differs across populations with individuals of African ancestry having a reduced risk than individuals of European (EU) ancestry. Further, single‐nuclei RNAseq analysis in autopsy samples from AD APOEε4 homozygotes with EU Local Ancestry (LA) had a significantly increased APOEε4 expression compared to those with African LA, particularly in astrocytes. To test the functional consequences of elevated APOE4 expression on astrocytes, we examined the effect of APOE4 overexpression in inducible pluripotent stem cell (iPSC) derived astrocytes (iAstrocytes).MethodiPSC were derived from European and African LA AD individuals homozygous for APOEε4/ε4. These APOEε4/ε4 iPSC were differentiated into astrocytes (iAstrocytes) which were transduced with a lentiviral construct overexpressing APOEε4 or a control vector. RNAseq analysis was performed to identify differentially expressed genes followed by pathway analyses.ResultiPSC lines were derived, validated for pluripotency, and differentiated into iAstrocytes. Preliminary analysis of transcriptional effects ofApoEe4 overexpression in iAstrocytes showed alterations in gene expression patterns, including the down regulation of the inflammatory markers THBS1 and CLDN11 which had both been shown to be downregulated in AD, the mitochondrial‐related gene NDUFA4L2 shown to be dysregulated in AD, as well as SFRP2 (Wnt modulator involved in TREM2 processing). Upregulated genes included RGMA (accumulates in amyloid plaques), as well as TNC and CECR2. Pathway analysis showed an enrichment for extracellular matrix (ECM)‐receptor interaction, PI3K‐Akt signaling, and TGF‐beta signaling pathways. Interestingly, the transcriptional response to APOEε4 overexpression has an ancestry‐specific component in these iAstrocytes; with some genes dysregulated exclusively in African ancestry iAstrocytes such as ZBTB4 and PRND, and others only in European iAstrocytes, including MYBPHL and VWF.ConclusionThe overexpression of APOEε4 in iAstrocytes resulted in alteration in gene regulatory patterns, including the ECM and key signaling pathways across ancestries (EU and AF). In addition, gene expression differences were identified between ancestries. Further analyses of these ancestry‐specific transcriptional differences may help to elucidate the mechanisms that drive the differential AD risk seen in APOEε4 individuals across ancestries.