bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cognitive dispersion as a function of cognitive reserve: influence on cognition and functional connectivity in a healthy middle‐aged population
Authors: Mulet‐Pons Lídia , Vaqué‐Alcázar Lídia , Solé‐Padullés Cristina , Cabello‐Toscano María , Abellaneda‐Pérez Kilian , Cattaneo Gabriele , Sánchez Javier Solana , Alviarez‐Schulze Vanessa , Tormos‐Muñoz Josep M. , Pascual‐Leone Alvaro , Bartrés‐Faz David 
Published: June 2023

AbstractBackgroundCognitive dispersion index (CDI), a measure of intraindividual variability across neuropsychological tests, is considered a sensitive marker of prodromic stages of Alzheimer’s Disease (Halliday et al. J. Intell 2018;6(1):12). CDI has been negatively associated with cognitive reserve (CR), another factor that influences the risk of dementia (Stern et al. Alzh&Dement 2020;16(9):1305‐1311). Nevertheless, how these two elements interact with each other and are linked with cognition and brain state (e.g., functional connectivity), remains unclear. Our aim was to investigate whether CDI has a differential influence on cognitive performance (CP) and on resting‐state functional connectivity (rsFC) as a function of CR level, in a healthy middle‐aged sample.MethodFive hundred forty‐four healthy volunteers (aged 53.11±7.10 years; 269 female) from the Barcelona Brain Health Initiative cohort (BBHI, https://bbhi.cat/en), were stratified by CR (median = 14) into High CR (HCR, N = 230) and Low CR (LCR, N = 314) using the cognitive reserve questionnaire (CRQ; Rami et al. Rev Neurol 2011;52(4):195‐201). CDI was extracted by intraindividual standard deviation method (Costa et al. Clinic Neuropsychol 2019;33(2):369‐389) and CP was calculated as a global cognition composite score including episodic memory, speed of processing and executive function tests. Functional magnetic resonance imaging (fMRI) was acquired, and measures of rsFC within networks were computed through Shirer atlas (Shirer et al. Cerebral Cortex 2012;22(1):158‐165). Statistical analyses were based on univariate ANCOVA GLMs, and partial correlations adjusted by age and gender.ResultThough no significant group interaction was found, a negative correlation between CDI and CP was identified for the HCR group (r = ‐0.170,p = 0.010; Fig.1A). On fMRI there was a significant group difference (HCR vs. LCR) in the association between CDI and rsFC in anterior salience network (aSN: F = 5.005,p = 0.026), where only HCR participants showed a significant negative association between CDI and aSN rsFC values (r = ‐0.187,p = 0.010; Fig.1B&C).ConclusionOur findings suggested that CDI has a clearly measurable effect on HCR participants, both in terms of its effect on CP and on rsFC. These results highlight the value of considering CDI measurements when performing neuropsychological assessments in middle‐aged individuals, particularly in those with high CR estimates.
A novel, humanized late‐onset Alzheimer’s disease mouse model expressing APOEe4, Trem2*R47H, and amyloid‐beta
Authors: Kotredes Kevin P , Oblak Adrian L , Pandey Ravi S , Territo Paul R , Rizzo Stacey J Sukoff , Carter Gregory W , Sasner Michael , Howell Gareth R , Lamb Bruce T 
Published: June 2023

AbstractBackgroundLate‐onset Alzheimer’s disease (LOAD) is the most common form of dementia without an approved therapy. Transgenic overexpression animal models do not effectively produce the heterogeneity observed clinically in LOAD patients and thus are not ideal for therapy development. Hence, the Model Organism Development and Evaluation for Late‐onset AD (MODEL‐AD) Center is developing, characterizing, and distributing novel mouse models expressing humanized, clinically relevant risk factors. Analysis of aging LOAD2 mice that better phenocopy human disease will inform the further development of subsequent generations of models and reveal more appropriate molecular targets useful in the treatment of LOAD.MethodTwo risk factors of LOAD, APOEe4 and Trem2*R47H, were incorporated into C57BL/6J mice along with humanized amyloid‐beta to produce the LOAD2 model. Mice were aged up to 24 months. In some mice, high‐fat diet replaced normal mouse chow. An animal phenotyping pipeline was employed to qualify and align with neurodegenerative disease states and phenotypes observed in human patients. In vivo imaging in addition to behavior and wellness assays were performed, as were analyses of blood and brain tissue for risk‐factor‐related alterations in neuropathology, transcriptomics, metabolomics, and proteomics.ResultAged LOAD2 mice on high‐fat diet present altered cytokine profiles in the brain, and peripherally, however no overt hippocampal pathology nor differences in long‐term potentiation were observed. Expression of human amyloid did not yield plaque formation in 18‐month mice. High‐fat diet was a strong determinant during behavioral phenotyping. Correlation of transcriptional profiling with human AMP‐AD modules determined individual and synergistic effects between genetic and environmental risk factors compared to human data. Continuing efforts to dissect the clinically‐relevant downstream effects of sex, age, genotype, and diet in these animals remain.ConclusionThe MODEL‐AD consortium has established the LOAD2 mouse model to study the effects of genetic and environmental risk factors of LOAD. This strain serves as a platform for the incorporation of additional AD risk factors (both genetic and environmental) to more closely align phenotypes in the mouse to outcomes observed in the clinic. Here we show the evidence of emerging disease pathology in an animal model exposed to genetic and environmental risk factors.
Incidence of subjective cognitive decline in a private practice memory clinic
Authors: Pippenger Mark A 
Published: June 2023

AbstractBackgroundSubjective Cognitive Decline (SCD) has been one focus of interest in dementia research, partly because of the concept that some people with SCD may be in the earliest stage of Alzheimer Disease (AD). The prevalence of SCD has been reported as ranging from 15‐54%, but most estimates come either from population‐based studies or from academic Memory Clinics. The author is the sole provider in a Memory Clinic established in a private‐practice healthcare company in a large US city, and evaluates all new patient referrals for cognitive complaints.MethodAll new patient evaluations for referrals to the Novant Health Memory Clinic in Charlotte, NC, for a period of one year (2021), were reviewed. The number of cases diagnosed as having AD, the number diagnosed with Mild Cognitive Impairment (MCI), and the number with SCD, were tabulated. AD and MCI were diagnosed according to the clinical criteria from the National Institute on Aging and Alzheimer’s Association. Diagnosis of SCD was made according to the criteria published by the Subjective Cognitive Decline Initiative (SCD‐I) Working Group.ResultDuring 2021, there were a total of 886 new patient evaluations in the Memory Clinic. Of those, 323 (36%) patients met clinical criteria for AD, 272 (31%) met criteria for MCI, and 211 (24%) for SCD.ConclusionSCD is relatively common in the private practice Memory Clinic setting. This could afford a potential to identify those people without dementia, who are at risk for later developing AD. The high prevalence of SCD may also create a market for unproven treatments for memory loss.
Modality matters for health disparity groups on the Montreal Cognitive Assessment (MoCA): Findings from the Einstein Aging Study (EAS)
Authors: Wang Cuiling , Nester Caroline O. , Chang Katherine H , Rabin Laura , Ezzati Ali , Lipton Richard B. , Katz Mindy J. 
Published: June 2023

AbstractBackgroundThe Telephone‐Montreal Cognitive Assessment (T‐MoCA) is a widely‐used, remotely administered cognitive screen. The T‐MoCA demonstrates adequate psychometric properties and may be used when standard, in‐person administration of the MoCA is not feasible (Katz et al., 2020). There is a critical need to investigate the agreement of the T‐MoCA across administration modalities (in‐person versus telehealth) among ethnically and racially diverse populations.MethodsThe Einstein Aging Study (EAS) includes a community‐based of racially/ethnically diverse community‐dwelling individuals, ≥ age 70 from the Bronx, NY. Participants (N = 424) were free of dementia at enrollment and completed the T‐MoCA along with in‐person neuropsychological tests including the MoCA‐22, which excludes items unsuitable for telephone administration paralleling the T‐MoCA (Table 1). Intraclass correlation coefficients (ICCs) between T‐MoCA and MoCA‐22 were used to measure agreement. Linear mixed effects models were applied to compare mean scores and ICCs among ethnic/racial groups, with and without adjusting for age, gender, education and depressive symptoms.ResultsParticipants were on average 78.2 years, 65.8% female, 47.6% non‐Hispanic White, 38.0% non‐Hispanic Black, and 14.4% Hispanic. There was no significant difference between mean T‐MoCA and MoCA‐22 scores and no differential associations with age, gender, education, and depressive symptoms. For both modalities, NH Black (difference ‐1.54, p<.0001) and Hispanic (difference ‐2.04, p<.0001) groups demonstrated significantly lower scores compared to non‐Hispanic Whites (Table 2). As shown in Table 2, ICCs among non‐Hispanic White, non‐Hispanic Black, and Hispanic groups were 0.64, 0.50 and 0.42, respectively, and comparisons of ICCs to non‐Hispanic White were significantly lower in non‐Hispanic Black (p = 0.0495) and borderline significant in Hispanic participants (p = 0.0552). Findings were similar after adjusting for covariates.ConclusionThe agreement between telephone and in‐person modalities of the MoCA was weaker in non‐Hispanic Black and Hispanic participants (compared to non‐Hispanic White). Further investigation of factors and/or items that contribute to these lower correlations is warranted. Although the T‐MoCA and other remotely administered cognitive screens have the potential to broaden accessibility to marginalized groups, researchers must use caution when developing or selecting appropriate demographically adjusted norms and interpreting scores of diverse older adults.
Age‐related cognitive decline are manifested by decreased event‐related delta and theta oscillations
Authors: Düzenli Seren , Gündüz Duygu Hünerli , Yener Görsev 
Published: June 2023

AbstractBackgroundEvent‐related oscillations (EROs) during cognitive paradigms reflect several cognitive functions in the brain. Event‐related delta responses are related to signal detection and decision making processes whereas theta is associated with working memory and selective attention (Yener and Başar, 2013; Başar et al., 2016). During physiological aging, EROs may be altered. The aim of the current study was to investigate time‐frequency measurements of event‐related oscillations in younger and older healthy participants.MethodFifty‐nine healthy participants were included in this study. They were divided into two subgroups as younger and older according to the age median score. Thirty younger healthy participants (mean age 22.37 years; standard deviation: 2.85) and 25 older healthy adults (mean age 56.48 years; standard deviation: 9.71) were completed a visual oddball task during EEG recording. Event‐related band power was assessed using event‐related spectral perturbation. Inter‐trial coherence values were analyzed by phase‐locking measurements. Event‐related power and phase‐locking analysis were performed for delta (0.5‐3.5 Hz), and theta frequency band (4‐7 Hz) over frontal (F3, Fz, F4), central (C3, Cz, C4), parietal (P3, Pz, P4), occipital (O1, Oz, O2) electrode locations. Repeated measures of ANOVA were used for statistical analysis.ResultThere were main GROUP effects for both event‐related delta [F(1,53) = 6.328, p = .015, ηp
2 = .107, Figure 1] and theta power [F(1,53) = 28.069, p<.001, ηp
2 = .346, Figure 2], indicating older healthy adults had reduced power values compared to younger healthy individuals (for all; p<.016). Furthermore, an interaction effect of Anterior‐Posterior Electrode Location x Group was found for theta power [F(3,159) = 13.869, p<.001, ηp
2 = .207], showing older healthy individuals had reductions in all electrode locations (for all; p<.017). Lastly, event‐related theta phase‐locking values were found to be reduced in older healthy adults [F(1,53) = 5.512, p = .023, ηp
2 = .094, Figure 3].ConclusionThe present study demonstrated older healthy participants had decreased event‐related delta and theta responses during visual oddball paradigm. These reductions may be explained by the alterations in cognitive capacities such as working memory/attention and decline in processing information during healthy aging.
Acknowledgement: The inclusion of younger healthy participants in this study was supported by Ankara University Scientific Research Projects Coordination Unit (Project Number: 16L02000001).
Neurologic manifestations in hospitalized patients with COVID‐19
Authors: Thakkar Kajal , Goldberg Alan , Gomez Joanne S , Suboc Tisha Marie , de Lavallaz Jeanne M Du Fay , Bouroukas Athina , Volgman Annabelle Santos , Williams Kim Allan , Aggarwal Neelum T. 
Published: June 2023

AbstractBackgroundTo investigate the effect of pre‐existing neurological symptoms and disease in coronavirus disease 2019 (COVID‐19) health outcomes in a large Illinois‐based cohort.MethodA multicenter retrospective study analyzed differences in a cohort of COVID‐19 positive patients with and without baseline neurological symptoms or disease admitted to RUSH University Systems for Health from March to November 2020. We measured sex and health outcome differences in hospitalization rates, symptoms during initial admission, complications, readmissions, and mortality of the two groups.ResultOf the total of 1708 hospitalized COVID‐19 positive patients (mean age: 58.04, 930 males) — 31% [527] patients had a history of neurological symptoms and/or disease, 9% [140] with dementia. Nonspecific symptoms during hospitalization including myalgia (19%), headache (11%), epilepsy (0.8%), tremors (3%), and abdominal pain (11%) were reported more frequently in patients with a neurologic history. Female patients with pre‐existing neurological conditions were hospitalized more than their male counterparts (40% versus 24%). Compared to those with no neurological conditions, patients with neurological conditions had higher rates of complications, such as acute myocardial infarction (13% vs. 8%; p = 0.002) and deep vein thrombosis/pulmonary embolism (14% vs. 10%; p = 0.02). Multivariate analysis showed that history of stroke and migraines are independently associated with readmission to a hospital floor (generalized linear model, z = 2.092, z = 3.320, p = 0.036, p < 0.001, respectively); of those readmitted, 13% had a history of dementia. Of the patients that died in hospital, 6% had a history of dementia.ConclusionNeurologic manifestations are common in hospitalized COVID‐19 positive patients and are associated with higher rates of complications during hospitalization. The increasing evidence for SARS CoV‐2’s impact on the central nervous system raises important questions on the long‐term consequences of this virus to patients with pre‐existing brain injury.
Learning from anti‐tau antibody clinical trials using computer simulation of spatial tau propagation
Authors: Geerts Hugo , Bergeler Silke , Walker Mike , Spiros Athan 
Published: June 2023

AbstractBackgroundBased on the tau spreading hypothesis, anti‐tau antibodies have been developed that can bind to and eliminate the misfolded tau protein during the short extracellular period. However, trials with tau antibodies have come up short in improving clinical outcome in Progressive Supranuclear Palsy (PSP) or Alzheimer’s Disease (AD). It is unclear whether the negative outcomes were due to insufficient target engagement and to what extent the change of tau CSF biomarkers reflected the brain pharmacodynamics.MethodA Quantitative Systems Pharmacology (QSP) computer platform of tau biology has been developed including tau species diversity and their respective concentration, neuronal activity‐dependent tau secretion, tau binding to membrane surface receptors HSPG and LRP1, tau‐antibody binding and subsequent internalization of tau at the synaptic cleft. This model is combined with a Physiology‐Based PharmacoKinetic (PBPK) model to derive brain target exposure of tau antibodies. In addition, a PBPK model is used to simulate the level of plasma and CSF biomarkers.ResultThe platform was calibrated with preclinical in‐vitro cellular assays and after injection of brain extract in Transgene mouse models and was further humanized using published data on seed‐competent tau from postmortem AD brain at different Braak stages. Combining the extracellular antibody exposure, the spatial dimensions and the dynamics of tau secretion, diffusion and binding to the membrane surface receptors, the model suggests that a very limited fraction (10‐20%) of misfolded tau protein can be captured by antibodies and cleared. Even less reduction (5‐10%) is predicted for Progressive Supranuclear Palsy due to the higher affinity of PSP‐4R tau for membrane surface receptors. The reductions in misfolded tau protein are greatest in earlier stages of the disease. With regard to epitope selection, we identify conditions where high specificity (i.e. monomeric vs misfolded tau) is superior to high sensitivity (affinity).ConclusionAdvanced Quantitative Systems Pharmacology computer modeling combining drug exposure dynamics with mechanistic modeling allows to (1) generate testable hypotheses for the outcomes of current therapeutic interventions, (2) support improved clinical trial designs in terms of dosing, patient selection, background amyloid therapy and disease stage and (3) ultimately prioritize targets for addressing tau pathology.
Identifying prognostic factors of dementia in individuals with mild cognitive impairment (MCI): Are statistical models adequate?
Authors: Wang Meng , Sajobi Tolulope , Ganesh Aravind , Seitz Dallas , Chekouo Thierry , Forkert Nils D , Borrie Michael , Camicioli Richard , Hsiung Ging‐Yuek Robin , Masellis Mario , Moorhouse Paige , Hogan David B , Trataglia Maria Carmela , Ismail Zahinoor , Smith Eric E. 
Published: June 2023

AbstractBackgroundIdentifying prognostic factors of MCI to dementia conversion is crucial. Most risk scores are developed based on selected variables using data‐driven methods from available variables in patient data. However, there is mixed evidence about the reliability of predictors selected based on data alone. Structured expert elicitation (SEE) is one approach to elicit clinician expert knowledge about relevant predictors for dementia risk. This study aims to identify critical predictors of dementia risk in persons with MCI from both SEE and random survival forests (RSF) and compare the differences between the two approaches.MethodClinical expert knowledge was quantified using SEE methodology: 11 experts (6 neurologists, 3 geriatricians, and 2 geriatric psychiatrists) were recruited to complete two rounds of surveys to rank predictors of dementia risk. RSF variable importance was used to assess the rank order of the potential predictors, according to the corresponding reduction of predictive accuracy when the predictor is replaced with its random permutation value risk using data from the Prospective Registry for Persons with Memory Symptoms of the Cognitive Neurosciences Clinic at the University of Calgary (N = 273; 26 potential predictors).ResultAccording to experts, the SEE revealed age and cerebrospinal fluid profile patterns consistent with Alzheimer’s disease (AD) as the two most important predictors of dementia risk in persons with MCI. In contrast, data‐driven RSF approach, using information from routine clinical practice without AD biomarkers, identified the Consortium to Establish a Registry for AD total score and the Montreal cognitive assessment (MoCA) total score as the most important predictors. Both approaches identified four common variables (among the top 10 predictors) included age, signs of parkinsonism, MoCA total score, and behaviour impairment.ConclusionOur findings revealed discrepancies between a data‐driven approach and SEE in identifying significant predictors of dementia in people with MCI. The SEE identified some crucial predictors, such as AD biomarker status, that are not routinely collected in registries and observational studies or available in widespread practice. Most published risk scores are not used in practice. This study offers a possible explanation: what is important to clinicians may be not included in the risk scores.
A large genetic screen in flies uncovers human modifiers of Aβ42 and tau toxicity
Authors: Varte Vanlalrinchhani , Munkelwitz Jeremy W , Scott Raymond , Limas Diego E Rincon 
Published: June 2023

AbstractBackgroundAlzheimer’s disease (AD) is a multifactorial neurodegenerative disorder characterized by dementia and cognitive decline due to progressive cerebral cortical atrophy. Brains of AD patients are characterized by the accumulation of microscopic extracellular amyloid‐beta (Aβ) plaques and intracellular neurofibrillary tangles composed of hyperphosphorylated tau. The deposition of Aβ42, which is one of the fragments of amyloid precursor protein (APP), has been known to play a role in initiating the events leading to the formation of amyloid and subsequently hyperphosphorylation of tau. However, animal models expressing either Aβ42 or tau individually do not mimic the complexity of the human condition. Indeed, recent evidence suggests that Aβ42 and pathological tau interact synergistically to modulate neurotoxicity in AD.MethodTo shed light on their concerted roles in AD pathogenesis and to discover pathways mediating Aβ42 and tau interactions, we generated transgenic flies co‐expressing human Aβ42 fused to a signal peptide along with the longest wild‐type tau isoform.ResultOverexpression of Aβ42 or tau in Drosophila using the UAS‐Gal4 system causes mild to the moderate rough eye. In comparison, co‐expression of Aβ42 with tau causes severe roughening and reduction of the eye size. The level of neuronal cell death in eye tissues was also significantly enhanced in flies co‐expressing Aβ42 and tau. To identify pathways mediating Aβ42+tau interactions, we are currently using the Aβ42+tau eye phenotype as platform to screen 1,500 UAS lines expressing a variety of human genes.ConclusionWe have identified few enhancers and suppressors not previously known to be involved in AD pathogenesis, which will be helpful to uncover new molecular pathways and potential therapeutic targets. This work is supported by NIH grant R21AG069050 to DERL.