bluuebunny/crossref_metadata_2025_split huggingface dataset:
Generation of microglia‐containing APOE4 cerebral organoids as a model of Down syndrome associated Alzheimer’s disease
Authors: Summers Rose , Johnson Noah R , Dooling Breanna , Potter Huntington 
Published: December 2023

AbstractBackgroundDown syndrome (DS) is among the most common forms of familial Alzheimer’s disease (AD), resulting from triplication of the amyloid precursor protein (APP) gene on chromosome 21 which leads to increased amyloid beta (Aβ) peptide accumulation in the brain. As a result, all people with DS will develop Aβ plaques and tau tangles by the age of 40, and the majority will eventually develop AD‐related cognitive decline. Carrying the e4 allele of the apolipoprotein E gene (APOE), APOE4, because it catalyzes the formation of neurotoxic Aβ oligimers. The combination of APOE4 and trisomy 21 results in a very high risk for DS associated AD. APOE4 has also been shown to drive altered microglial activity in the AD brain, leading to increased neuroinflammation, neurodegeneration and cognitive decline. Studying mechanisms underlying APOE4‐microglial interactions could lead to identification of new therapeutic targets for DS‐AD treatments. Microglia‐containing cerebral organoids (MCOs) derived from human induced pluripotent stem cells (hiPSCs) with both trisomy 21 and APOE4 would offer a distinct advantage over prior models.MethodIsogenic hiPSC disomic or trisomic for chromosome 21 from an individual mosaic for trisomy 21 and carrying the APOE3/3 genotype and CRISPR‐Cas9 gene editing was then used to generate hiPSCs with the APOE4/4 genotype. hiPSCs were then differentiated into hematopoetic progenitor cells (HPCs) and neural progenitor cells (NPCs) and co‐cultured at a 7:3 ratio (NPCs:HPCs) to form MCOs.ResultControl cerebral organoids (COs) lacking HPCs were reduced in size compared to age‐matched MCOs, suggesting the successful integration of HPCs with NPCs during co‐culture. Immunohistochemical analysis showed neural rosettes characteristic of COs and shows that neurons, astrocytes and microglia were all present in MCOs throughout development.ConclusionWe have developed a novel model for DS‐AD that will be critical for identifying APOE4‐microglial interactions as a therapeutic target in DS‐AD. These MCOs may be used in pre‐clinical testing of potential therapies, which may lead to treatment for the highly vulnerable population of APOE4 carriers with DS‐AD.
RESILIEN‐T: Field testing a lifestyle coaching app for subjective cognitive decline
Authors: Astell Arlene J. , Bernick Alana , Acenas Maria , Saney Danielle , Swaminathan Swathi , Casaccia Sara , Scalise Lorenzo , Pollini Alessandro , Oberholzer Pierre , van Megen Xandra , Hermanns Joost , Krijger Regina , Felici Elisa , Sabatini Tania , Rossi Lorena 
Published: December 2023

AbstractBackgroundLinks between subjective cognitive decline (SCD) and dementia are encouraging older adults to optimize their physical and mental health. Self‐managing lifestyle factors such as physical activity, healthy eating, social and cognitive stimulation can contribute to this optimization. RESILIEN‐T is an international project co‐producing and field testing an integrated goal‐setting and coaching app with and for older adults.MethodPhase 1 iterative co‐production of the user interface, goal‐setting and coaching elements. Phase 2 mixed methods pilot trial with 15 participants with SCD (mean age 80 years) in four countries evaluated the prototype for two months. Phase 3 mixed‐methods field trial with 221 participants with SCD across four countries randomly assigned to the RESILIEN‐T intervention or control arm for three months. Minimum Data set of SCD (MAC‐Q) and health (EQ5D‐5L) were completed at baseline and end of trial, when usability (System Usability Scale) was also assessed.ResultAll pilot participants reported positive experiences with RESILIEN‐T, enjoying the easy‐to‐use interface and the daily suggestions to keep active. In the field study the MAC‐Q score improved in both groups, but this was only significant in the RESILIEN‐T group who improved significantly more than the control group. Health score improvement was higher in the RESILIEN‐T group but not significantly and SUS score was acceptable (71.9).ConclusionThe RESILIEN‐T project confirms the interest among older adults with SCD of self‐managing lifestyle factors to promote cognitive health. The results of this short‐term intervention show promise for people with SCD to positively impact their cognition
Evaluating cognitive phenotypes and associations with neuroimaging biomarkers of dementia in a sample of aging individuals using unsupervised machine learning
Authors: Rudolph Marc D. , Ma Da , Bateman James R. , Hughes Timothy M. , Sachs Bonnie C. , Whitlow Christopher T , Sai Kiran K. Solingapuram , Craft Suzanne , Lockhart Samuel N. 
Published: December 2023

AbstractBackgroundOtherwise cognitively normal individuals can experience age‐related cognitive dysfunction and may present with heterogenous patterns of cognitive impairment. There is limited knowledge regarding the presence and stability of cognitive subtypes observed in individuals with mild cognitive impairment and dementia (e.g., dysexecutive, non‐amnestic). Further, the extent to which cognitive subtypes related to age‐ and dementia‐related neuroimaging biomarkers is uncertain.MethodThis study sought to evaluate the presence and composition of cognitive subtypes in a large diverse community sample of aging individuals without dementia (NC; Baseline N = 337; Table 1). Participants enrolled in the Wake Forest ADRC and completed an annual battery of cognitive assessments (Uniform Data Set; NACC), the Mini‐Mental State Exam (MMSE), and Clinical Diagnostic Rating Scale (CDR). Unsupervised machine learning (e.g., clustering: hierarchical, k‐means, and k‐medoids algorithms; 1000 bootstrap iterations; majority voting rule) was applied to the battery of cognitive assessments. Demographic characteristics and neuroimaging measures of amyloid deposition (global PiB PET SUVr; Aβ‐PET), total brain volume (BVOL), diffusion‐weighted fractional anisotropy (FA), and NODDI freewater (FW) were compared across prospective clusters using general linear models. Highly correlated cognitive metrics (r>.85) were removed prior to analysis.ResultCluster analyses using baseline cognitive scores suggested NC participants could be partitioned into two to eight clusters; two primary clusters representing one large homogenous group of relatively unimpaired individuals and another heterogenous cluster composed of 4‐7 possible cognitive subgroups (Figure 1). The two‐cluster solution partitioned NC participants into higher and lower cognitive performers. Across cluster solutions, lower performing individuals were older, had higher Aβ‐PET, and lower total brain volume on average (p<.05; Figure 2).ConclusionWe did not observe well‐defined clusters representing distinct cognitive subtypes reported in previous studies (e.g., dysexecutive, amnestic, visuospatial). However, a heterogenous subset of NC participants exhibited substantial variability across assessments. Three‐ and four‐cluster solutions identified individuals with greater impairment in executive functioning, and verbal learning and memory respectively. Findings highlight the need to model complex patterns of cognitive abilities in otherwise healthy older adults. Future longitudinal work will assess how health information and neuroimaging biomarkers of dementia contribute to the composition and stability of cognitively defined subgroups.
Impact of sex and ApoE4 on the longitudinal association of plasma ptau‐181 and NFL with cognitive decline in non‐demented older adults
Authors: Nallapu Bhargav Teja , Petersen Kellen K. , Lipton Richard B. , Ezzati Ali 
Published: December 2023

AbstractBackgroundAPOE4 is a strong genetic risk factor for Alzheimer’s disease (AD). Sex‐dependent differences has been shown in AD pathophysiology and clinical course. Here, we aim to assess the association between longitudinal changes in ptau‐181 and neurofilament light protein (NfL) and concurrent changes in cognitive measures in non‐demented individuals and to evaluate if this association is impacted by sex and ApoE4 status.MethodParticipants (N = 738) were non‐demented (cognitively unimpaired or mild cognitive impairment) older adults from the Alzheimer’s Disease Neuroimaging Initiative (ADNI, N = 738) with up to 4ys of longitudinal data. Linear Mixed Effects (LME) models were used to study the effect of ptau‐181 and NFL on cognition as measured by the cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS‐cog11; Range 0‐70) and Clinical Dementia Rating, sum of boxes (CDR‐SB). Sex by time and APOE4 by time interactions were assessed in the models for the entire sample. Analyses was repeated after separately stratifying sample by sex and APOE4.ResultAt baseline, both ADAS‐11 and CDRSB values correlated with plasma p‐Tau181 and NfL measures (Table 1). The longitudinal change in plasma p‐Tau181 correlated only with baseline CDR‐SB while that of NfL correlated with baseline ADAS‐11. The APOE4*time interaction, but not sex‐time interaction, were significant in LME models of both p‐Tau181 and NFL (Table 2). When stratified by sex, in females longitudinal increase in p‐Tau181 was associated with cognitive decline measured by both ADAS‐11 and CDR‐SB. In males, longitudinal increase in p‐Tau181 was associated with increase in ADAS‐11 scores and NfL was associated with cognitive decline on both outcomes. When stratified by APOE4 status, longitudinal changes in plasma biomarkers were only associated with cognitive decline in the APOE4+ subsample.ConclusionPlasma NfL and pTau increase during early AD and can be used to monitor disease progression. The relationship between increase in plasma ptau‐181 and NFL levels and worsening of cognition is affected by APOE4 status.
Basal Forebrain Volume Mediates the Relationship Between Cortical Cholinergic Level and Cognition in Parkinson’s Disease
Authors: Crowley Sam Joseph , Kanel Prabesh , Roytman Stiven , Bohnen Nicolaas I , Hampstead Benjamin M. 
Published: December 2023

AbstractBackgroundCholinergic denervation is associated with cognitive decline in Parkinson’s disease (PD). This is likely due to atrophy of the basal forebrain, which is affected by α‐synuclein early in PD. Studies show associations between basal forebrain volume and cognition and between cortical cholinergic levels and cognition, but no study has determined if basal forebrain volume mediates the relationship between cholinergic levels and cognition.MethodParticipants included 103 non‐demented individuals with idiopathic PD (M:F = 76:27; Age = 67.3±7.6 yrs) who underwent structural MRI and [18F] fluoroethoxybenzovesamicol (FEOBV) cholinergic PET imaging. We averaged cholinergic PET values in 7 ROIs derived from FreeSurfer in a prior publication (van der Zee, 2022): 1) bilateral temporoparietal regions (PC1); 2) subcortical and limbic regions (PC2); 3) bilateral cingulate regions (PC3); 4) left frontal regions (PC4); 5) right frontal and temporal regions (PC5); 6) cerebellum (PC6); and 7) bilateral entorhinal and left temporal regions (PC7). We used an executive function composite (Stroop Color‐Word Inhibition/Switching, Trail Making Switching, Letter Fluency, WASI‐IV Matrix Reasoning) and a verbal recall measure (CVLT‐II Long Delay Free Recall) as outcome variables.ResultAfter controlling for age, basal forebrain volume fully mediated the associations between PC3 (indirect effect:β = 0.075, 95% CI = 0.002‐0.166; total effect:β = 0.235, p = .02; direct effect:β = 0.161, p = .13) and PC7 (indirect effect:β = 0.069, 95% CI = 0.007‐0.141; total effect:β = 0.212, p = .02; direct effect: β = 0.142, p = .15) and executive function. Basal forebrain volume fully mediated the association between PC1 and verbal recall (indirect effect:β = 0.079, 95% CI = 0.014‐0.163; total effect:β = 0.222, p = .02; direct effect:β = 0.141, p = .14) and partially mediated the association between PC3 (indirect effect:β = 0.076, 95% CI = 0.003‐0.156; total effect:β = 0.345, p<.001; direct effect:β = 0.269, p = .01), PC5 (indirect effect:β = 0.070, 95% CI = 0.003‐0.150; total effect:β = 0.341, p<.001; direct effect:β = 0.271, p<.01), and PC7 (indirect effect:β = 0.072, 95% CI = 0.005‐0.150; total effect:β = 0.298, p<.01; direct effect:β = 0.226, p = .02) and verbal recall.ConclusionThis is the first study to demonstrate that basal forebrain volume mediates the relationship between cholinergic level and cognitive function. Future studies will investigate additional cognitive domains and measure structural integrity of individual nuclei in the basal forebrain.
Relationship between metabolic syndrome, sleep quality and cognitive impairment
Authors: Olivar Natividad , Dunovits Cynthia , Rojo Matias , Muchnik Carolina , Germani Sandra , Brusco Luis Ignacio 
Published: December 2023

AbstractBackgroundMetabolic syndrome is a risk factor for cardiovascular diseases, which have been related to cognitive impairment and Alzheimer disease. Sleep disorders in older adults have a negative impact on cognitive performance. However, a link between metabolic syndrome, sleep, and cognitive decline has not been established.MethodA retrospective cross‐sectional study was carried out. Information was collected from clinical histories about demographic, metabolic parameters, sleep diaries, neurocognitive evaluation and neuroimaging studies. For statistical analyses, chi‐square tests of association were included for categorical variables (age, sex, educational level, social economy status (SES), hypertension, diabetes, BMI, depression, anxiety, smoking, sedentary lifestyle) for each memory problem. A binary logistic regression model was used to predict the probabilities of memory problems. Which was built including each variable independently.ResultsThe logistic regression revealed that women and low educational level were associated with increased memory difficulties over time (odds ratio [OR] = 5.3, p < 0.001). Depression was associated with increased odds of memory problems (OR = 3.8, p <0.001). When the sleep quality variable was added, it was observed that the poor sleep quality partially reduced the impact of age, gender, and depression on memory. However, all continued to present an OR greater than 1. Of the medical conditions, type 2 diabetes and hypertension showed a significant interaction (OR = 1.7, p < 0.001).ConclusionWe believe that there is an association between metabolic state, sleep quality and cognitive impairment. in such a way that those with metabolic disorders and poor sleep quality have decreased cognitive performance.
Disclosure of Amyloid PET results to Cognitively Impaired and Unimpaired Participants Enrolled in Alzheimer’s Disease Research Studies
Authors: O'Connell Abigail H , Fischer Eric , Latham Lauren , Bateman James R. , Craft Suzanne , Lockhart Samuel N. , Rundle Melissa M. , Okonmah‐Obazee Stephanie E. , Sai Kiran K. Solingapuram , Williams Benjamin J. 
Published: December 2023

AbstractBackgroundPrior studies have demonstrated the safety of amyloid PET scan disclosure to research participants. However, existing research has been conducted in predominantly white, cognitively intact, and highly educated samples. The Wake Forest Alzheimer’s Disease Research Center (ADRC) implemented a protocol to provide amyloid PET disclosure to a diverse cohort of participants with and without cognitive impairment.MethodEligible participants who complete an amyloid PET scan at the Wake Forest ADRC may consent to receive amyloid PET scan results. Prior to consent, participants are informed of possible results (elevated/not elevated) and how these results are related to Alzheimer’s disease (AD) risk. The disclosure process involves three phases: 1) pre‐disclosure assessment of anxiety and depression, 2) feedback session with a trained clinician, and 3) post‐disclosure completion of the Impact of Events Scale (IES). Additionally, a qualitative survey was developed to collect participant feedback following the disclosure session.Results170 participants (CN = 103, MCI = 48, dementia = 17, other = 2) have received amyloid disclosure; age: 70.5 (7.9); education: 15.7 (2.7); 62% female; 87% white). There was a statistically significant difference in IES scores between CN/MCI participants (CN = 4.3(7.2), MCI = 8.6(10.7), t(165) = 2.8, p = 0.005). There was no significant difference between IES scores in other cognitive pairs (CN‐Dementia = t(165) = 1.5, p = 0.134, MCI‐Dementia = t(165) = 0.36, p = 0.729).Post‐disclosure feedback surveys were completed by 41 participants (age = 71.7 (6.7) years, education = 15.9 (2.4) years, 63% female, 83% white) who reported (1 = strongly disagree, 5 = strongly agree) that receiving their results was a positive (M = 4.6 (0.6)) and informative (M = 4.78 (0.47)) experience, and given what they now know, they would chose to receive their results again (M = 4.58 (0.87)). There were no significant differences in responses between cognitive groups. Participants also reported that knowledge of their PET results will impact their future thoughts, feelings, and behaviors (M = 4.00 (1.02)).ConclusionAmyloid disclosure is safe and well tolerated by a diverse cohort, though participants with MCI reported higher IES scores post‐disclosure. Participants reported positive experiences on a feedback questionnaire and would choose to receive results again.
Detection of brain Tau deposition across Braak stages using plasma pTau181, MRI, and cognitive function assessments
Authors: Devanarayan Viswanath , Charil Arnaud , Sachdev Pallavi , Hu Helen , Nelson Todd , Koyama Akihiko , Reyderman Larisa , Hampel Harald , Irizarry Michael C. , Dhadda Shobha , Kramer Lynn D 
Published: December 2023

AbstractBackgroundNon‐invasive methods for detecting neurofibrillary tangles that spread throughout the brain are needed for efficiently screening patients in Alzheimer’s disease (AD) clinical trials. This can be accomplished via machine‐learning models using baseline clinical characteristics. Adding plasma pTau181 and brain region volumes may improve detection accuracy.MethodRegional MK6240 Tau‐PET SUVR data were available for 312 Amyloid‐positive patients from a clinical trial (182 MCI, 130 mild AD, 131 Tau‐negative, 181 Tau‐positive). Over 90% of the Tau‐positive subjects were in Braak 3‐6. Plasma pTau181 was measured using Simoa assay. Data were split randomly into 70%‐30% for training and testing purposes. Tau positivity for each Braak stage was defined via the one‐sided upper 99% confidence limit of a subset of 70 subjects with background SUVR.Signatures for detecting Tau positivity in Braak 3‐6 and for further discriminating Braak 3‐4 and 5‐6 were derived via the stochastic gradient boosting algorithm and Bayesian ordinal logistic regression respectively. Demographics (age, gender, BMI), ApoE4 status, and cognitive assessments were included, and the added value of plasma pTau181 and volumetric MRI measures were assessed. Prediction performance was assessed via 10‐fold cross‐validation in the training set followed by evaluation in the test set.ResultSignatures comprising psychometric data, ApoE4 status, and demographics achieved 76% accuracy (ROC AUC = 80.4%) for detecting Tau positivity in Braak 3‐6, and 60.8% accuracy for discriminating Braak 3‐4 versus 5‐6. Adding plasma pTau181 significantly improved the accuracy to 82.2% (ROC AUC = 86.6%, p<0.05) in Braak 3‐6, and to 67.6% accuracy (p<0.05) for Braak 3‐4 versus 5‐6. Besides plasma pTau181, key predictors were delayed word recall, ADAS‐cog‐14, BMI, CDR‐SB, and ApoE4 genotype.Detection accuracy of Tau positivity in Braak 3‐4 versus the spread to Braak 5‐6 improved significantly from 67.6% to 74.6% (p<0.05) when combining MRI data with plasma pTau181, ApoE4, and demographics. Key MRI predictors were the thickness and volume of the inferior parietal cortex. Adding cognitive assessments did not improve the detection accuracy.ConclusionThese results demonstrate the potential of non‐invasive investigations such as plasma pTau181, cognitive performance, and MRI data for detecting Tau deposition throughout the brain along the Braak stages.
Views and perceptions of amyloid imaging in a preclinical Alzheimer’s disease trial
Authors: Ritchie Marina , Raman Rema , Ernstrom Karin , Wang Shunran , Donohue Michael C. , Aisen Paul S. S , Henley David , Romano Gary , Novak Gerald P , Brashear H. Robert , Sperling Reisa A. , Grill Joshua D. 
Published: December 2023

AbstractBackgroundStudies have shown that many cognitively unimpaired older individuals are interested in learning their Alzheimer’s disease (AD) biomarker results. Yet, little is known about what motivates participation in preclinical AD trials that require amyloid biomarker testing and disclosure, and whether these motivations differ by biomarker results (elevated or not‐elevated amyloid).MethodUsing data from the EARLY trial, a preclinical AD trial testing the safety and efficacy of a BACE1 inhibitor, we analyzed participant responses on the Views and Perceptions of Amyloid Imaging (VPAI) scale (Table 1) that was collected during the screening process; that is, before undergoing biomarker testing and disclosure. Participants were asked to rate how important 9 potential reasons for seeking amyloid imaging were to them. Response options included “not at all” (1), “a little” (2), “somewhat” (3), “very” (4), and “extremely” (5). We categorized raw scores into binary responses; those with high endorsement (scores ≥4) and those with low‐to‐moderate endorsement (scores <4). We stratified participant responses by amyloid group to examine whether their biomarker status impacted participant item‐level VPAI scores.ResultPrior to biomarker testing and disclosure, participants most often endorsed the desire to contribute to research as a motivation to participate (Table 1). In general, the not‐elevated amyloid group had higher endorsement for the VPAI items than the elevated amyloid group. The proportions of participants endorsing “confirm feeling that I might be developing dementia” and “preparing family members” were observed to be higher among participants with elevated compared to not‐elevated amyloid; whereas “curiosity” was endorsed by a higher proportion of the not‐elevated amyloid group.ConclusionWhile there are individual differences in reasons for seeking an amyloid scan, preclinical AD trial participants may be largely motivated by altruistic factors. Differences in factors that motivate participants to learn biomarker results may be apparent between amyloid groups even before biomarker disclosure.