bluuebunny/crossref_metadata_2025_split huggingface dataset:
Lower baseline cerebral oxygen extraction and metabolic rate are associated with faster cognitive decline and brain atrophy over a longitudinal follow‐up period
Authors: Robb W Hudson , Khan Omair A. , Ahmed Humza A. , Cambronero Francis E. , Kim Darcie S , Houston Michelle , Shah Krish U , Pechman Kimberly R. , Liu Dandan , Gifford Katherine A. , Hohman Timothy J. , Jefferson Angela L. 
Published: December 2022

AbstractBackgroundOxygen extraction fraction (OEF), cerebral blood flow (CBF), and cerebral metabolic rate of oxygen (CMRO2) are complexly interrelated. Low OEF and CMRO2 are promising early indicators of Alzheimer’s disease (AD) pathophysiology. To better understand how alterations in cerebral oxygen utilization relate to abnormal brain aging, we investigated baseline oxygen metabolism variables (OEF, CBF, CMRO2) in relation to longitudinal cognition and brain structure, and if these associations were different among individuals at genetic risk for sporadic AD (i.e., apolipoprotein E (APOE)‐ε4 carriers).MethodsVanderbilt Memory and Aging Project participants (n=244, 74±7 years, mean follow‐up=3.7 years) underwent serial neuropsychological testing and multimodal 3T brain MRI. We used T2‐relaxation‐under‐spin‐tagging to calculate OEF and pseudo‐continuous arterial spin‐labeling to assess grey matter CBF. CMRO2 was calculated as: CMRO2=OEF*CBF*arterial oxygen content. Linear mixed‐effects regression models related time x oxygen metabolism variable (one predictor per model) to longitudinal cognitive and brain MRI outcomes. Models were adjusted for baseline age, sex, race/ethnicity, education, Framingham Stroke Risk Profile, cognitive status, intracranial volume (for MRI outcomes), APOE‐ε4 status, and time. Models were repeated testing anAPOE‐ε4 status x oxygen metabolism variable x time interaction term.ResultsLower baseline OEF was associated with faster hippocampal atrophy (p=0.02). Lower baseline CBF was associated with faster cortical thinning in regions susceptible to AD‐related neurodegeneration (p=0.008). Lower baseline CMRO2 was associated with faster language decline (p=0.01) and hippocampal atrophy (p=0.01) and inferior lateral ventricle volume increase (reflecting faster atrophy of adjacent tissue; p=0.02). OEF interacted with APOE‐ε4 status on executive function (p=0.002), language (p=0.006), and visuospatial performances (p=0.02), and inferior lateral ventricle volume (p=0.007). CBF interacted with APOE‐ε4 status on executive function performance (p=0.0003). CMRO2 interacted with APOE‐ε4 status on temporal lobe volume (p=0.03). In stratified models, lower baseline OEF and CMRO2 tended to relate to faster brain health decline among APOE‐ε4 carriers.ConclusionsLower OEF, CBF, and CMRO2 are associated with worse brain health trajectories over a 4‐year follow‐up. Assessing oxygen metabolism variables in combination may provide more comprehensive insight into longitudinal brain aging and serve as an early biomarker of disease, particularly among older adults at genetic risk for AD.FundingT32‐AG058524, IIRG‐08‐88733, R01‐AG034962, R01‐NS100980
ABCA7*V1599M variant in 5xFAD mice mediates differences in amyloid‐beta pathology and reactive gliosis
Authors: Butler Claire Ann , Javonillo Dominic I , Houchin Lauren A , Kawauchi Shimako , Phan Jimmy , Da Cunha Celia , Tran Katelynn , Milinkeviciute Giedre , Tenner Andrea J , LaFerla Frank , MacGregor Grant R , Green Kim N 
Published: December 2022

AbstractBackgroundIn several large genome‐wide association studies (GWAS), genetic polymorphisms of ATP‐binding cassette transporter subfamily A member 7 (Abca7) have been identified as a risk factor for late‐onset Alzheimer’s Disease (LOAD). ABCA7 is a member of a family of ATP‐binding cassette (ABC) transporters and functions as a transmembrane protein mediating the release of cholesterols and phospholipids from cellular membranes. Previous studies have also proposed its role in mediating phagocytic clearance of amyloid beta (Aβ) oligomers within macrophages in the brain.MethodTo study the effects of ABCA7 on the development of AD relevant pathologies we introduced an equivalent coding sequence change that has been identified as a risk variant for LOAD (V1613M) into the C57BL/6 mouse genome using CRISPR/Cas9 (V1599M). We set out to characterize the ABCA7V1599M variant and investigate its impact on AD pathology when crossed with 5xFAD transgenic mice, generating four distinct groups: WT, ABCA7V1599M homozygous, 5xFAD, and 5xFAD x ABCA7V1599M homozygous. Characterization was performed using histological staining and biochemical approaches.ResultCoronal brain sections from 4‐month‐old mice (n=5‐6 mice/sex/genotype) revealed significantly reduced burden of dense‐core Aβ plaques in confocal images of both subiculum and visual cortical regions of 5xFAD x ABCA7V1599M mice compared to 5xFAD mice characterized by reduced Thioflavin‐S staining. Biochemical analysis mirrored these findings and demonstrated reductions of both soluble and insoluble Aβ40 and Aβ42 levels within these same brain regions. To examine reactive gliosis to plaque burden, we immuno‐stained for ionized calcium binding adaptor molecule 1 (IBA1) and glial fibrillary protein (GFAP) to visualize microglia and reactive astrocytes, respectively. Confocal analysis revealed reduced densities of both IBA1+ microglia and GFAP+ reactive astrocytes within subiculum and cortical regions of 5xFAD x ABCA7V1599M mice compared to 5xFAD mice. We also found reduced plaque‐associated neuritic damage in 5xFAD x ABCA7V1599M mice upon immuno‐staining for lysosome‐associated membrane glycoprotein 1 (LAMP1) to examine neuritic dystrophyConclusionTogether, these results characterize the effects of the Abca7em1Aduci
allele and its ABCA7V1599M missense mutation on 5xFAD‐mediated pathology, specifically in Aβ plaque development, glial morphology, and neuritic damage.
The role of Tau RNA complex formation in tau function and tauopathy disorders
Authors: McMillan Pamela , Benbow Sarah J , Uhrich Rikki , Baum Misa , Strovas Timothy J , Baker Jeremy D , Kraemer Brian C 
Published: December 2022

AbstractBackgroundPathological tau characterizes Alzheimer’s disease, FTLD‐tau, and other tauopathy disorders. Canonically, tau functions as a microtubule binding and stabilizing protein. The molecular mechanisms of tau mediated neurodegeneration remain incompletely understood. Recent studies from our group and others have shown that RNA binding proteins modulate the severity of tau pathology. Further, RNA has previously been demonstrated to drive tau aggregation in vitro. We hypothesize that tau itself may interact physically with RNA and/or RNA binding proteins, thereby altering tau MT related functions.MethodsWe employed biophysical and biochemical approaches to measure tau/RNA binding. To generate reagents for characterizing tau RNA complexes (TRCs) in human disease, we raised monoclonal antibodies as a tool to assess the formation of tau RNA complexes in human disease and animal models of disease.ResultsWe show tau binds single stranded RNA with high affinity but low sequence specificity. Tau seems to bind RNA homopolymers with higher affinity that with tubulin (α/β) dimers. Since poly(A) RNA is the most abundant RNA homopolymer in living cells and known poly(A) RNA binding proteins modulate tauopathy phenotypes, we investigated the ability of poly(A) RNA to form complexes with tau in vitro. Incubation of purified tau with poly(A) RNA promotes the formation of TRCs that appear as oligomeric tau species (N= ∼6‐20) by size exclusion chromatography. Tau binding to RNA inhibits tau microtubule polymerization activity. We generated a monoclonal antibody against purified TRCs and generated a conformation dependent monoclonal antibody called TRC35 that recognizes purified AD fibril tau over recombinant non‐fibrillar tau. Poly(A) binding proteins control TRC35+ accumulation in tau transgenic mice. We observe TRC35+ tau deposits in a wide variety of tauopathy disorders including Alzheimer’s disease, progressive supranuclear palsy, corticobasal degeneration, frontotemporal lobar degeneration, and Pick’s disease.ConclusionsTau binds RNA with high affinity. This tau RNA binding activity antagonizes tau action as microtubule stabilizing protein. Tau RNA binding stimulates tau oligomerization and the formation of a disease relevant conformational epitope. Poly(A) RNA binding proteins modulate TRC35+ deposits of pathological tau in model systems and Alzheimer’ s disease. TRC35+ lesions occur in diverse tauopathy disorders.
English language proficiency and patterns of use as related to cognitive change in native Spanish speakers of the Hispanics/Latinos of the Hispanic Community Health Study/Study of Latinos‐Investigation of Neurocognitive Aging
Authors: Lamar Melissa , Tarraf Wassim , Wu Benson , Perreira Krista M , Lipton Richard B. , Khambaty Tasneem , Cai Jianwen , Llabre Maria M , Gallo Linda C , Daviglus Martha L , González Hector M 
Published: December 2022

AbstractBackgroundGiven mixed results regarding the role of bilingualism in cognitive aging, investigators are increasingly studying continuous measures of bilingualism (e.g., levels of language proficiency or use) as opposed to a dichotomous “yes/no” one, to better characterize the bilingual experience. We investigated associations of continuous measures of bilingualism and cognition.MethodEligible Hispanic Community Health Study/Study of Latinos (HCHS/SOL) participants self‐reported their and their parents’ birth outside the 50 United States and Spanish as their first language, and used Spanish for baseline cognitive testing at their HCHS/SOL visit (2008‐2011) and comparable cognitive testing 7‐years later as part of the SOL‐Investigation of Neurocognitive Aging (SOL‐INCA; 2015–2018). Composite scores for baseline self‐reported Spanish/English language proficiency (reading/speaking) and patterns of use (thinking/socializing) were rated using a Likert scale from 1 = only Spanish to 4 = English>Spanish. Cognitive testing at both visits included test‐specific and a global composite score(s) of verbal learning and memory, Word Fluency, and Digit Symbol Substitution (DSS). Survey linear regression models examined the associations between our two bilingualism scores (separately) and cognition (at follow‐up, and standardized measures of 7‐year change) adjusting for age, sex, education, depressive symptoms, income, Hispanic/Latino background, and field center.ResultThere were 4,005 eligible participants (unweighted mean SOL‐INCA population age∼56 years, 56% female). Higher levels of second‐language (English) proficiency (β = 0.050, SE = 0.015, p<0.001) and patterns of use (β = 0.035, SE = 0.010, p<0.001) were associated with higher levels of global cognition at follow‐up (Figure), specifically, Fluency and DSS (p‐values<0.001). Only higher levels of second‐language proficiency were associated with better than predicted change in cognition, specifically, Fluency (β = 0.060, SE = 0.023, p<0.01).ConclusionIn an analytic sample of mid‐ to late‐life native Spanish speakers currently living in the US, second‐language (English) proficiency and patterns of use at baseline were associated with better cognitive outcomes over seven years of follow‐up. Associations of bilingualism composites and cognition suggest distinctions in the bilingual experience may differentially relate to level versus 7‐year change in cognition for Hispanics/Latinos. Investigations of foreign language learning on cognition in older adults, some of which have found no cognitive benefit, may be enhanced by using continuous measures of second‐language proficiency and, perhaps, patterns of language use.
Effects of multilingualism on cognition among older Indian adults in the nationally representative LASI‐DAD study
Authors: Petrosyan Sarah , Renteria Miguel Arce , Manly Jennifer J , Narayanan Shrikanth , Lee Jinkook 
Published: December 2022

AbstractBackgroundMultilingualism is hypothesized to protect late life cognition such that older multilinguals demonstrate better cognitive functioning compared to monolinguals. However, several studies have failed to find evidence of a multilingual advantage among aging populations. Methodological differences such as inconsistent accounting of critical environmental and sociocultural factors (e.g., educational experiences, lifecourse socioeconomic status, residential urbanicity) associated with multilingualism may explain these inconsistent findings. Furthermore, the lack of research conducted in low‐ and middle‐income countries limit the generalizability of these findings. India offers a unique opportunity to study the role of multilingualism in cognitive aging, given its rich linguistic and sociocultural diversity.MethodThe current study utilizes a national representative sample of older Indian adults from the Harmonized Diagnostic Assessment of Dementia for the Longitudinal Study in India (LASI‐DAD). Respondents included 4,088 adults aged 60 and over, speaking over 40 different languages and dialects (73.6% monolingual, 26.4% report speaking ≥2 languages). We evaluated the association of multilingualism with global cognitive functioning after accounting for critical demographic and health factors such as age, sex, urbanicity, total consumption, diabetes, and hearing loss, among others. We also assessed whether this association differed by region and education.ResultOverall, multilingualism was associated with better global cognition after controlling for demographic and health confounds. There was an interaction between region and multilingualism such that there was a greater benefit of multilingualism on cognition in South India compared to North India. The effect of multilingualism on cognition also differed by level of education, with the greatest benefit among multilinguals with higher levels of education. However, stratified models demonstrated that multilingualism was positively associated with cognition, regardless of education, in South India, whereas this association was only observed among those with higher educational attainment in North India.ConclusionIn India, multilingualism was associated with better cognition, but this association differed by region and educational attainment. Future research should investigate regional variations in lifecourse factors that may explain the differences in the multilingual advantage observed across North and South India. Furthermore, future studies should deconstruct multilingualism (e.g., age of acquisition, proficiency) in order to evaluate their association with cognition cross‐sectionally and longitudinally.
Bilingualism Appears to be Protective Against Cognitive Decline Related to Amyloid Burden in Mexican Americans: An HABS‐HD Study
Authors: Petersen Melissa , Hall James , Johnson Leigh , Braskie Meredith N , Yaffe Kristine , Rissman Robert A. , Toga Arthur W. , O'Bryant Sid E. ,   Health and Aging Brain Study‐ Health Disparities (HABS‐HD) Study Team
Published: December 2022

AbstractBackgroundBilingualism has been considered to exert protective effects from neurodegeneration and age‐related diseases such as Alzheimer’s Disease (AD). The protective effect is considered to be due to differences in grey and white matter between monolingual and bilinguals; however, no work to date has looked at differences in additional AD brain pathology. The aim of this study was to fill this gap and examine among Mexican Americans the impact of amyloid burden on cognitive functioning stratified by language status.MethodData were analyzed on n = 111 Mexican Americans (n = 45 Monolingual; n = 66 Bilingual) participants from a study of health disparities. All participants underwent cognitive testing and PET amyloid imaging, which was conducted using a Siemens Biograph Vision 450 PET/CT scanner with florbetaben. SUVR regions of interest (ROIs) included Frontal, Anterior/Posterior Cingulate, Lateral Parietal, and Lateral Temporal cortex and were derived using the cerebellum as a reference region in FreeSurfer. Linear regressions were conducted with each ROI included as a predictor variable and cognitive functioning as the outcome variable. Covariates included age, sex, and education. Analyses were split by language status (monolingual, bilingual).ResultAmong monolingual Mexican Americans, higher Global and Lateral Temporal SUVR were significantly related to poorer performance across measures of executive functioning (p = 0.039 and p = 0.038) and processing speed (p = 0.013 and p = 0.027); Global SUVR showed a trend towards significance on a measure of verbal fluency (p = 0.052). In the same group, Frontal SUVR was significant related to poorer performance across measures of global cognition (p = 0.046), executive functioning (p = 0.015), processing speed (p = 0.007) and verbal fluency (p = 0.037), the latter two were also significantly related to Anterior/Posterior Cingulate SUVR (p = 0.008 and p = 0.029). In addition, higher Lateral Parietal SUVR was significantly related to poorer performance on a measure of processing speed (p = 0.030). Among bilingual Mexican Americans, Frontal and Anterior/Posterior Cingulate SUVR were positively associated with semantic fluency (p = 0.049 and p = 0.043).ConclusionAmyloid burden was found to be related to poorer cognitive functioning across multiple domains specifically among monolinguals. Those who identified as bilingual did not present with the same relationship between amyloid uptake and cognitive functioning further supporting the potential protective effect of bilingualism.
Automatic Extraction of Oculographic Signals as Digital Biomarkers for Alzheimer's Disease
Authors: Meyer Trevor , Moro‐Velazquez Laureano , Motley Seneca , Butala Ankur , Paul Ashley , Samus Quincy M , Irazoqui Pedro , Dehak Najim , Oh Esther S 
Published: December 2022

AbstractBackgroundSimilar to other neurological diseases, subtle early neurological changes that occur in Alzheimer’s Disease (AD) are difficult to quantify and track objectively. One relevant bio‐signal is eye movement, as it presents a unique window into cognitive processes as a direct measure of real‐time inputs to the brain. Eye‐tracking allows us to estimate timestamped activity of neural function and begin to infer and quantify attention, reprocessing (eg. word revisits), and many other aspects relevant to assessing AD. The goal of this study was to investigate the saccadic movements and trial progress during administration of the Stroop test in AD compared to normal controls.Method5 AD subjects and 12 age‐matched cognitively normal controls were recruited from the Johns Hopkins Memory and Alzheimer’s Treatment Center and the Movement Disorders Clinic at the Johns Hopkins University School of Medicine. An Eyelink Portable Duo in head‐free‐to‐move mode was used to track eye movements. Movement of the eyes were analyzed by automatically segmenting saccade movements throughout a trial. We then analyzed the eye movements in the context of cognitive performance, by identifying when subjects progress to each word in the Stroop test. We compared the performance of each group using a Wilcoxon RankSum test with the SciPy package using Python.ResultPreliminary results show that 60% (3/5) of AD subjects were unable to complete the Stroop task in 80 seconds. Individuals with AD had more saccades (p=0.105) with greater saccadic overshoot (p=0.092) and a greater maximum saccade velocity (p=0.035) on average compared to cognitively normal controls. AD subjects also took much longer to complete the first (p=0.114) and second lines (p=0.092) compared to healthy controls, suggesting initial confusion and hesitation.ConclusionAD subjects change their gaze more often with greater speed and less precision than age‐matched controls. These data demonstrate feasibility of using automatic quantitative evaluation of eye movements in AD. In the future, we will determine the utility of using this tool for early detection of AD and tracking its progression, along with combining other measures such as voice and handwriting (multimodal) to provide insights into early physiological changes in AD.
Considering sex in mild‐to‐moderate Alzheimer’s disease clinical trials: A meta‐analysis of ADCS trials
Authors: Dahdoul Thabat A , Gillen Daniel L. , Grill Joshua D 
Published: December 2022

AbstractBackgroundNearly two thirds (62%) of Alzheimer’s disease (AD) patients in the United States are women (Nebel 2018; Rajan, 2021). Our goal in this project was to assess whether women are proportionately represented in AD clinical trials and whether sex was associated with other baseline patient characteristics.MethodsWe used data from nine mild‐to‐moderate AD trials conducted by the AD Cooperative Study (ADCS): Docosahexaenoic acid (DHA), FYN Kinase, Homocysteine, Huperzine (Hu), IV immunoglobulin (IVIg), nonsteroidal anti‐inflammatory drugs (NSAIDs), Resveratrol (Res), Simvastatin, Valproate. Sample sizes ranged from 120 (Res) to 642 (IVIg) participants. We compared the proportions of females enrolled to disease prevalence estimates. We conducted a random effects meta‐analysis to estimate female participation rates across the nine trials. Specifically, we used a generalized linear mixed effects model with logit link and random intercept to estimate the marginal and trial specific prevalence of female participants. To compare participant characteristics by sex we pooled samples across trials and used unadjusted chi‐square (categorical variables) and t‐tests (continuous variables).ResultsThe proportion of females enrolled exceeded 50% in each trial, with the exception of the FYN Kinase trial (44.7%). In all but the Hu trial, the rate of female enrollment was less than the estimated female disease prevalence. The estimated prevalence of female participants across all trials was estimated to be 56% (95% CI 0.53 to 0.58) (Figure 1). Females were similar to males in terms of age and APOE genotypes. Compared to males, females had lower education, less often enrolled with a spouse, less often lived with their study partner, and more often were from an underrepresented racial or ethnic group.ConclusionsThough these trials recruited more females than males, on average, women were still underrepresented compared to national disease prevalence estimates. Female and male participants exhibited psychosocial differences in education, race, and study partner characteristics that could affect trial outcomes and should be further investigated.