bluuebunny/crossref_metadata_2025_split huggingface dataset:
MCI in Caribbean Hispanics shows increased impairment in attention and working memory domains relative to non‐Hispanic White individuals
Authors: McInerney Katalina , Zaman Andrew , Mena Pedro R. , Adams Larry D. , Tejada Sergio J. , Sanchez Jose Javier , Celis Katrina , Hamilton‐Nelson Kara L. , Feliciano‐Astacio Briseida E. , Rajabli Farid , Beecham Gary W. , Vance Jeffery M. , Cuccaro Michael L. , Pericak‐Vance Margaret A. 
Published: December 2023

AbstractBackgroundPatterns of cognitive performance associated with different stages of dementia have been primarily studied in Non‐Hispanic White (NHW) populations. This study compares patterns of cognitive performance, on a brief neuropsychological battery, in Caribbean Hispanic (CH) and NHW individuals with mild cognitive impairment, based on Clinical Dementia Rating (CDR) staging scores.MethodOur data included 427 individuals including 299 self‐identified CH (mean age = 76.0; 69.6% female; mean education = 11.9) and 128 NHW (mean age = 72.9; 61.7% female; mean education = 13.8) who completed the CDR and a brief neuropsychological battery. Participants with other medical conditions known to impact cognition were excluded. Sex‐, age‐, and education‐adjusted Z‐scores were calculated for all cognitive tests (Logical Memory (Immediate and Delayed recall), Digit Span (Forward and Backward), and Verbal Fluency (Animals and Vegetables)). ANOVAs were used to examine the effects of ethnicity (NHW, CH) and CDR Global Score (0.5, 1.0) on the adjusted Z‐scores for all cognitive tests. CDR score distribution was adjusted through factorial ANOVA (ethnicity x CDR). Descriptive analyses included independent t‐tests to examine differences between ethnicity groups on age, sex, education, percent AD, percent Unclear, and CDR Global Score.ResultThere was a main effect of ethnicity on Digit Span Forward (p < 0.001), Digit Span Backward (p < 0.001), and Verbal Fluency – Vegetables (p < 0.01), where CH individuals showed greater impairment regardless of Global CDR score. We found a main effect of Global CDR score on all cognitive tests, where individuals with Global CDR score of 1.0 demonstrated more impairment than individuals with a Global CDR score of 0.5. No ethnicity x CDR interactions were significant.ConclusionOur sample of older CH and NHW individuals, presumed to have mild cognitive impairments based on CDR staging, did not differ in memory abilities. However, the CH group scored significantly lower on measures of attention and working memory. Finally, semantic fluency performance was variable and possibly influenced by cultural familiarity with different semantic categories. Among older CH individuals with mild dementia, cognitive difficulties may extend beyond memory problems and include attentional and executive function difficulties. These findings have clinical implications for diagnosis and management of CH patients.
Association of contemporary dementia diagnosis rate with clinician characteristics: Evidence from Medicare claims
Authors: Liu Ying , Becker Andrew , Jun Hankyung , Wallick Christopher , Mattke Soeren 
Published: December 2023

AbstractBackgroundPopulation‐level gap and disparities are documented for the dementia diagnosis. Little is known, however, the extent to which clinician’s characteristics, including the characteristics of the patient population they serve, are associated with their likelihood of adequately diagnosing dementia, after accounting for patient characteristics.MethodWe used the 100% Medicare fee‐for‐service and Advantage Plan data from 2017 to 2019. Patients were attributed to primary care clinicians based on plurality of office visits. We determined each clinician’s observed number of patients with a diagnosis of dementia of any etiology and estimated the expected number of cases with a predictive model using patient characteristics (age, sex, race/ethnicity, whether dually eligible for Medicare and Medicaid). The ratio between the clinician’s observed and expected diagnosis rates (O/E ratio) serves as performance measure for diagnostic accuracy. We calculated 95% confidence intervals (CI) around those O/E ratios and categorized those whose 95% CI included 1 as diagnosing dementia at an adequate rate and those whose 95% CI did not reach 1 as underdiagnosing dementia. We then used logistic regression to predict a clinician’s likelihood of having adequate diagnosing compared to under‐diagnosing using clinician characteristics: their attributed patient panel’s composition on race/ethnicity, dually eligible, and having had annual wellness visit, urban‐rural location of the practice, the clinician’s specialty, and state fixed effects.ResultAmong 194,699 included clinicians, those serving more White (Odds Ratio [OR] = 1.50 for 10 percentage points [pp] increase, p<0.001), fewer Black (OR = 0.94 for 10 pp increase, p<0.001) or Hispanic patients (OR = 0.98 for 10 pp increase, p = 0.003), and fewer duals (OR = 0.82 for 10 pp increase, p<.001) were more likely to have an adequate diagnosis rate than under‐diagnosing. Clinicians who practiced outside of metropolitan areas were less likely to have an adequate diagnosis rate (compared to metropolitan, OR = 0.91, p = 0.025 for micropolitan; OR = 0.75, p<0.001 for small town; OR = 0.63, p<0.001 for rural areas). No association is seen with percent of patients having annual wellness visit (OR = 1.00 for 10 pp increase, p = 0.913).ConclusionPrimary care clinicians who serve racial/ethnic minority or dually eligible patients and practice outside of big cities may under‐detect dementia cases.
Posterior cingulate cortex microRNA alterations in cognitive resilience, mild cognitive impairment, and Alzheimer’s disease
Authors: Counts Scott E. , Beck John S. , Maloney Bryan , Malek‐Ahmadi Michael H. , Kockmanski Joseph J. , Ginsberg Stephen D. , Mufson Elliott J. , Lahiri Debomoy K. 
Published: December 2023

AbstractBackgroundMicroRNA (miRNA) dysregulation is linked to Alzheimer’s disease (AD) pathophysiology. We recently reported a role for miR‐298 and miR‐20b in AD risk and amyloid and tau metabolism. To examine the extent to which miRNAs are dysregulated during the earliest stages of AD, we quantified miRNA transcript levels in postmortem samples of posterior cingulate cortex (PCC), a default mode network (DMN) hub that underlies autobiographical memory, in normal subjects and those who died within the AD continuum.MethodPCC samples were obtained from Rush ROS/MAP participants who came to autopsy with a diagnosis of a) no cognitive impairment and low pathology (NCI‐LP, Braak stage I/II, n = 12), b) NCI with high pathology (NCI‐HP, Braak stage IV, representing cognitive resilience, n = 8), c) mild cognitive impairment (MCI, n = 10), or d) dementia due to AD (n = 9). Illumina‐based sequencing of total RNA was performed and trimmed reads with a size of 15‐31 bases were analyzed.ResultDifferential expression analysis (FDR ≤ 0.04) revealed 42 miRNAs significantly dysregulated among the NCI (independent of Braak stage), MCI, and AD groups. Two miRNAs, miR‐99a (FDR‐adjusted p = 0.01) and miR‐664b (p = 0.005), were downregulated in AD vs NCI and MCI, while miR‐30a (p = 0.006), miR‐374a (p = 0.004), and miR‐501 (p = 0.005) were significantly upregulated in MCI vs. NCI and AD. Three miRNAs were significantly downregulated in NCI‐HP vs. NCI‐LP: miR‐103a (p = 0.04), miR‐211 (p = 0.03), and miR‐4443 (p = 0.03). These miRNAs may operate in resilience‐related pathways. Correlation analysis revealed that decreasing PCC levels of miR‐664b levels were associated with poorer performance on antemortem tests of episodic memory (r = 0.41, p = 0.009), semantic memory (r = 0.44, p = 0.004), and visuospatial ability (r = 0.45, p = 0.004).ConclusionTaken together, these data may identify potential pathogenic or protective miRNA‐related mechanisms contributing to PCC and DMN function during the progression of AD, which may inform biomarker and intervention strategies. Ongoing analysis will identify functional pathway enrichment and miRNA targets.
Interactome‐guided machine learning modeling reveals information embedded in blood plasma protein‐protein interactions in Alzheimer’s Disease patients treated by the complex plasma fraction GRF6019
Authors: Nanasi Tibor , Braithwaite Steven P , Lehallier Benoit 
Published: December 2023

AbstractBackgroundThe relevance of plasma fraction treatment to reverse age‐related conditions was underlined by our previous pre‐clinical results. In two Phase 2 clinical trials (GRF6019‐201 and GRF6019‐202), patients with Alzheimer’s Disease (AD) were treated with the complex plasma fraction GRF6019, which was determined to be safe and well‐tolerated. Interestingly, no cognitive decline and minimal functional decline were observed. While GRF6019 treatment was associated with a quick and widespread proteomics response, lasting molecular changes were more subtle. Here, we developed new machine learning models guided by protein‐protein interaction (PPI) information to deeper understand the molecular effects of GRF6019 plasma fraction treatment.MethodMore than 7k proteins were measured in 120 plasma samples from treated subjects enrolled in the GRF6019‐201 and GRF6019‐202 trials (n = 21 and 18, respectively) using the Somascan assay. Interacting protein pairs were curated from STRING and OmniPath PPI databases. For each protein‐protein interaction, linear Support Vector Machine (SVM) models were trained to separate before and after treatment samples based on measured protein levels and compared to single‐protein models. Proteins were ranked based on their individual performance and their gain of performance when combined with interaction partnersResultProteasome‐associated elements were overrepresented among proteins with top individual performance. Interaction models provided more details about related processes involving ubiquitination. Furthermore, various other immune, hormonal, and neuronal terms found to be enriched among the top interactors.ConclusionComplex biological functions can be mapped into pathways which are composed of and regulated by PPIs. Biological functionality can be encoded in concentrations of individual proteins, also in relative concentrations of interacting proteins. Our results indicate that the latter aspect may contain a significant amount of complementary information, not accessible with traditional approaches analyzing proteins as independent entities. Consequently, the development and the application of novel system biology tools on blood plasma proteomics will help to better understand patients’ responses to treatment in clinical trials.
Relationship between Life’s essential 8 scores and cognitive decline in the ELSA‐Brasil cohort
Authors: Vidal‐Ferreira Naomi , Gonçalves Natalia G , Szlefj Claudia , Goulart Alessandra C. , Santos Itamar Souza , Duncan Bruce , Schmidt Maria Inês , Barreto Sandhi Maria , Caramelli Paulo , Feter Natan , Castilhos Raphael Machado , Drager Luciano Ferreira , Lotufo Paulo A , Bensenor Isabela M , Suemoto Claudia Kimie 
Published: December 2023

AbstractBackgroundLifestyle and cardiovascular risk factors were combined in the Life’s simple 7 (LS7) index to evaluate cardiovascular health, and this index has been previously associated with cognitive decline. The Life’s Essential 8 (LE8) is an update of LS7, which now includes sleep health as an additional factor. We aimed to verify the association between LE8 and cognitive decline during X years of follow‐up in 11,390 participants from a racially diverse sample.MethodIn this cohort study, LE8 score was measured based on diet, physical activity, nicotine exposure, sleep health, BMI, blood lipids, blood glucose, and blood pressure. Cognition was assessed in three waves four years apart from each other using the CERAD word list, semantic and phonemic verbal fluency, Trail Making Test B (TMT‐B), and a global composite score. We used inverse probability weighting to account for mortality and attrition bias and linear mixed models with random intercepts and slopes to verify the association between baseline LE8 score and cognitive decline. We tested the interaction between LE8 and age, sex, and race.ResultThe mean sample age was 51.4±8.9yo at baseline, 56% were women, and 43% Black. Higher baseline LE8 scores were associated with slower memory (β = 0.001; 95%CI = 0.000,0.002; p = 0.013), verbal fluency (β = 0.001; 95%CI = 0.000,0.002; p = 0.003), executive function (β = 0.004; 95%CI = 0.003,0.005; p<0.001), and global cognitive decline (β = 0.001; 95%CI = 0.001,0.002; p<0.001) (Table 1). Age (p < 0.001), sex (p < 0.001), and race (p < 0.001) were modifiers of the association between LE8 score and global cognitive decline (Figure 1), suggesting that in different socioeconomic profiles, this association might have different manifestations.ConclusionHigher baseline LE8 scores were associated with global and domain‐specific decline after eight years of follow‐up. Age, sex, and race were modifiers of this association, suggesting that it might differ based on the participant’s socioeconomic profile.
Florbetapir PET Uptake in White Matter in Aging and Alzheimer’s Disease
Authors: Bhargava Vedanshi , Luo Ji , Chen Yinghua , Ghisays Valentina , Malek‐Ahmadi Michael H. , Sohankar Javad , Lee Wendy , Protas Hillary D. , Reiman Eric M. , Su Yi 
Published: December 2023

AbstractBackgroundAmyloid PET tracers, typically used to track cerebral amyloid changes in Alzheimer’s Disease (AD) patients, have been recently suggested to measure cerebral white matter (WM) integrity due to structural similarity between myelin and amyloid. We previously reported significant associations of amyloid neuroimaging marker, Pittsburgh Compound B (PiB) PET, with WM hyperintensities as quantified by MRI and FLAIR data, in AD patients (Su et al. 2018, HAI). The goal of this study was to explore the association between Florbetapir (FBP) PET and WM integrity.MethodOur study population consisted of 673 participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) sorted into the following groups of clinical severity: (1) Normal Controls (NC) participants who are amyloid negative and cognitively normal (CDR = 0) (A‐CDR‐); (2) Preclinical (Pre) who are cognitively normal (CDR = 0) and amyloid positive (A+CDR0); (3) Symptomatic AD who are both CDR and amyloid positive (A+CDR+); and (4) Suspected Other Dementia group consisting of cognitively impaired but amyloid negative participants. We analyzed baseline biomarkers as function of stage of AD and age, comparing groups using ANOVA and Scheffe’s Post Hoc Analysis, and linear regression, respectively. Associations between white matter and amyloid FBP uptake were quantified using Pearson correlation with Least Trimmed Square (LTS) regression. Lastly, rate of change of amyloid and white matter uptake of FBP PET were quantified to assess longitudinal biomarker changes using a one sample t‐test.ResultCross‐sectionally, baseline FBP uptake in white matter significantly declines with age (p = 0.027) and advancing disease stage with significant differences found between the Preclinical and Symptomatic AD group (p<2.2E‐06); and NC and Symptomatic AD group (p<0.003). Significant associations were also observed between baseline FBP uptake in white matter and amyloid (p<0.001).Longitudinally, rate of change of FBP uptake in white matter progressively declined with advancing disease stage while rate of change of FBP uptake in amyloid increased and plateaued in the Symptomatic group of patients.ConclusionAltogether, our results show declining FBP uptake by white matter, both cross‐sectionally and longitudinally, through the stages of AD and with age. Our results could have methodological implications on the quantification of amyloid burden using WM as a reference region.
Number of completed exercise sessions is associated with slower brain atrophy in MCI over 12 months in the EXERT trial
Authors: Digma Leonardino A , Aslanyan Vahan , Brewer James B. , Bevins Elizabeth A , Katula Jeffrey A. , Chmelo Elizabeth , Hodge Heather , LaCroix Andrea Z. , Shadyab Aladdin H. , Jacobs Diane M. , Salmon David P. , Feldman Howard H. , Pa Judy , Baker Laura D 
Published: December 2023

AbstractBackgroundMid‐ and late‐life exercise has been associated with lower dementia risk. The EXERT trial tested whether aerobic training (AX), compared to stretching/balance/range‐of‐motion training (SBR), could slow cognitive decline in MCI. While no difference was detected between exercise arms, EXERT participants overall showed little cognitive change over 12 months. It is possible that the amount of exercise, rather than the type, may be protective against decline. In this exploratory, post‐hoc analysis of EXERT data, we assessed whether intervention adherence, operationalized as the number of supervised exercise sessions completed, was associated with slower brain atrophy over 12 months.Method194 EXERT participants with baseline and follow‐up MRI were included in this analysis. For each participant, the number of supervised exercise sessions of at least 40 minutes in duration completed during the first 12 months was determined. MRI data were processed using FreeSurfer. Repeated measures ANOVAs were conducted using regional volume or thickness as the dependent variable, and the interaction between number of sessions (continuous scale) and study visit as the independent variable. Baseline age and sex, as well as their interactions with time were included in the model. FDR‐adjusted p‐values <0.05 were considered significant.ResultGreater number of sessions completed was associated with less brain atrophy over 12 months in the hippocampus and parahippocampus, and less ventricular expansion in the lateral and inferior lateral ventricles (Table 1, Figure 1; FDR‐corrected p<0.05 for interaction term). Results remained unchanged when including exercise type (AX vs. SBR), baseline CDR‐SB, or baseline plasma Aβ42/40 in the model. Findings were similar when analyses were restricted to participants who completed the study prior to the onset of the COVID‐19 pandemic.ConclusionOur results show that higher adherence to a supervised exercise intervention over 12 months was associated with reduced brain atrophy in adults with amnestic MCI. These findings were obtained in post‐hoc, exploratory analyses, so causality should be interpreted with caution. EXERT was supported by the Alzheimer’s Disease Cooperative Study and funded by the National Institutes of Health grant U19‐AG010483.
Age but not education affects social decision‐making in the Ultimatum Game paradigm
Authors: Cassimiro Luciana , Cecchini Mario Amore , Cipolli Gabriela Cabett , Yassuda Monica Sanches 
Published: December 2023

AbstractBackgroundDecision‐making is a key cognitive ability for autonomy and quality of life in old age and it may be influenced by social context. Social decision‐making is often studied through the use of gaming paradigms, where participants allocate resources between themselves and others based on predefined rules. In a version of the Ultimatum Game (UG) decision‐making behaviour was modulated in response to fairness of monetary offers and social context of monetary offers designed to produce either prosocial or punishing behaviours. Previously, patients with behavioural variant frontotemporal dementia were reported to be impaired in the UG when they needed to modulate their decisions in response to social contextual information. The aim of the present study was to investigate whether social decision‐making evaluated by the UG is affected by age and education. It is relevant to know whether sociodemographic variables may bias UG results.MethodA total of 131 healthy adults participated ‐ 35 were young university students and 96 were older adults. The sample was divided into three age groups (17‐ 22, 60‐ 69, 70‐79 years old) and three education groups (4‐8, 9‐11, 12 or more years of education). Participants completed a health questionnaire and cognitive tests to ascertain normal cognitive status.ResultAge and education did not affect performance in fair monetary offers. Differences were observed in the unfair conditions. The older group (70‐79) accepted less frequently the Baseline unfair offers (without social context), when compared with the young and the 60‐69 group (young = 60‐69 > 70‐79). Regarding the Prosocial unfair and Punishing unfair conditions, older adults accepted such offers more frequently (young < 60‐69 = 70‐79). In other words, when a prosocial context (for instance, unemployment) was added to unfair monetary offers, older adults accepted them more frequently than younger adults. Education effects were not observed.ConclusionIn the context of social decision‐making, cognitively unimpaired older adults may show prosocial behaviors more frequently than younger adults. Findings suggested the UG is affected by age but not education.
Multivariate canonical correlation analysis to delineate ATN specific genetic variants in Alzheimer’s disease
Authors: Zhuang Xiaowei , Yang Zhengshi , Cordes Dietmar 
Published: December 2023

AbstractBackgroundGenome wide association studies (GWAS) in AD have been focused on clinically diagnosed case‐control subjects, and have identified more than 70 AD risk loci1‐3. The biological mechanisms underlying these genetic variants in AD remain unclear. In this study, we investigated the relationship between subjects’ genetic variants and AD biomarkers within the NIA‐AA ATN framework4 using a single holistic multivariate canonical correlation analysis (CCA) approach.Method932 subjects from the ADNI database5 with at least one 1) clinical visit; 2) 18F‐AV45 amyloid PET scan 3) structural MRI scan; 4) CSF sample; and 5) genotyping data were included in this integrated CCA analysis. More specifically, after imputation and quality control steps, 3323 single‐nucleotide‐polymorphism (SNP) with p‐values<1e‐4 in previous AD‐GWAS1 were included as genetic features. Following the ATN framework, subjects’ amyloid status were quantified by CSF‐derived amyloid beta 42 (Abeta42) values and amyloid PET‐derived standardized uptake value ratio (SUVR) values in major cortices; subjects’ tau status was represented by CSF‐derived phosphorylated tau values; and subjects’ neurodegenerative status were quantified using MRI‐derived cortical thickness measures from AD‐meta‐ROIs6. Total 16 measures were included as ATN biomarkers. Using CCA, we sought to estimate pairs of canonical components along which genetic variants and ATN biomarkers co‐vary in a similar way in these subjects7,8. Statistical significance of each canonical component was determined through the permutation inference9. We further examined SNPs and biomarkers that are most strongly correlated with each significant CCA component identified.ResultCCA analysis reveals two significant components that relate AD risk SNVs to ATN biomarkers (r = 0.6381 (p = 0.0002) and r = 0.5776 (p = 0.0046), Fig.1). The first component is most significantly contributed by amyloid biomarkers (Fig.2(A)), and top associated SNVs are centered around the APOE, APOC1, TOMM40, PVRL2 genes on chromosome 19 (Fig.2(B)), which are overrepresented in pathways related to amyloid formation and catabolic process. Furthermore, tau biomarkers significantly contribute to the second CCA component (Fig. 2(A)), and top associated SNVs are additionally involved in the regulation of neurofibrillary tangle assembly pathway.ConclusionUsing multivariate CCA method, we identified specific genetic variants covaried with the amyloid (A), tau (T) and neurodegeneration (N) biomarkers in AD, respectively.