bluuebunny/crossref_metadata_2025_split huggingface dataset:
Plasma biomarkers of neuroinflammation and vascular injury predict cognitive decline in patients with mild cognitive impairment
Authors: Trombetta Bianca A. , Kivisäkk Pia , Carlyle Becky C. , Magdamo Colin , Merrill Emily , Chibnik Lori B. , Serrano‐Pozo Alberto , Hyman Bradley T. , Das Sudeshna , Arnold Steven E. 
Published: December 2020

AbstractBackgroundThe development of robust blood‐based biomarkers for pathological and clinical characterization of Alzheimer’s disease (AD) is necessary, particularly as therapeutic approaches shift towards early intervention. Novel, ultra‐sensitive OlinkTM technology allows for high‐throughput quantification of protein signatures in biofluids. In this study, we examined the utility of this technology to identify plasma biomarkers associated with longitudinal cognitive performance in individuals presenting with mild cognitive impairment (MCI).Methods60 participants from the Massachusetts ADRC Longitudinal Cohort with a clinical diagnosis of MCI, baseline global CDR of 0.5, and at least five annual follow‐up evaluations were classified into two groups based on their global CDR trajectory: MCI‐decline (an increase in global CDR from 0.5 to 1) and MCI‐stable (no change in global CDR). Five OlinkTM Proximity Extension Assay (PEA) panels were assessed for technical reliability and used to quantify 460 plasma proteins at baseline visit. We built statistical models to identify proteins whose plasma levels were predictive of future cognitive decline, and used machine‐learning to evaluate the utility of these proteins for predicting conversion from MCI to dementia, relative to clinical and demographic predictors.ResultOlinkTM panels exhibited excellent technical precision and plate‐to‐plate replication. Of the 460 proteins measured, 60 did not pass quality control thresholds. A final model adjusting for age and sex identified 14 proteins with a significant fold‐change in MCI‐decline compared to MCI‐stable (p<0.05), including NfL, CX3CL1, M‐CSF, VEGF‐A, IL‐8, NOS3, TNFRSF12A, and PHOSPHO1. An additional 10 proteins approached significance (p<0.1), primarily representative of inflammatory and vascular processes. Addition of these proteins to a supervised classification model informed by baseline cognitive measured substantially improved the overall accuracy from 63% to 83.3% (AUC: 0.88, sensitivity: 0.76, specificity: 0.87).ConclusionOur findings suggest that plasma biomarkers of neuroinflammation and vascular injury have value as predictors of MCI‐to‐dementia progression. These circulating biomarkers may reflect CNS processes, blood‐brain barrier dysfunction, and/or systemic inflammation that drive AD associated pathophysiologies, or represent comorbid vascular pathologies. Developing a plasma biomarker panel could aid in prognostic deliberations by identifying MCI individuals at higher risk of progressing to dementia in clinical practice.
The relationships of grip strength and gait speed with cognitive function in a diverse cohort: Kaiser Healthy Aging and Diverse Life Experiences (KHANDLE) Study
Authors: George Kristen M. , Gilsanz Paola , Peterson Rachel , Glymour M. Maria , Mayeda Elizabeth Rose , Mungas Dan M. , Whitmer Rachel A. 
Published: December 2020

AbstractBackgroundGrip strength and gait speed, indicators of frailty, have been associated with poor cognitive outcomes. Whether there are differences in these associations by race/ethnicity is unknown. In the Kaiser Healthy Aging and Diverse Life Experiences (KHANDLE) Study, we examined the cross‐sectional associations of grip strength and gait speed with cognition.MethodKHANDLE aimed to evaluate how race/ethnicity and life‐course health influence late‐life brain health among community‐dwelling adults ages 65+ living in Northern California. Analysis included 1,353 Asian (24%), Black (26%), Latino (18%), and White (32%) participants. Grip strength (kg) was measured using a hand‐held dynamometer and gait speed measured a timed 4‐meter walk (m/s). Cognitive domains of verbal episodic memory, semantic memory, and executive function were measured using the Spanish and English Neuropsychological Assessment Scales (SENAS). Z‐standardized test scores were averaged for a global z‐score. Linear regression was used to assess the associations of grip strength and gait speed with cognition. Models were adjusted for demographic (age, education, income), physical (waist circumference), and behavioral risk factors (physical activity, smoking status, alcohol consumption). Gender and race/ethnicity interactions were tested separately.ResultParticipants had a mean age of 76 (SD=7) years and 58% were women. The associations of grip strength and gait speed with cognition did not differ by gender. A standard deviation (SD) increase in grip strength was associated with better global cognition [β=0.11(0.06, 0.15)]. This association did not differ by race/ethnicity and was similar across cognitive domains [executive β=0.07(0.03, 0.12); semantic β=0.12(0.07, 0.17); verbal β=0.06(0.01, 0.11)]. A SD decrease in gait speed was associated with worse global cognition [β=‐0.09(‐0.12, ‐0.06)] and associations were consistent across domains [executive β=‐0.08(‐0.11, ‐0.05); semantic β=‐0.08(‐0.11, ‐0.05); verbal β=‐0.06(‐0.09, ‐0.02)]. There were significant race/ethnicity interactions on the associations of gait speed with global cognition (p=0.001), executive function (p=0.02), and semantic memory (p=0.0004). Decreased gait speed was associated with worse cognition in these domains for Asians, Latinos, and Whites, but not associated in Blacks.ConclusionGrip strength and gait speed were cross‐sectionally associated with cognition. There were race/ethnicity differences in the association of gait speed with executive function, semantic memory, as well as global cognition.
Early adulthood and midlife cardiovascular risk factors and late‐life cognition in KHANDLE: A lifecourse study of a diverse cohort
Authors: Peterson Rachel , George Kristen M. , Gilsanz Paola , Mayeda Elizabeth Rose , Glymour M. Maria , Mungas Dan M. , DeCarli Charles , Whitmer Rachel A. 
Published: December 2020

AbstractBackgroundMidlife cardiovascular risks (CVR) are associated with late‐life cognition and dementia. Prior studies that examine early and midlife CVR on cognitive aging in Asians, Blacks, and Latinos are limited.MethodsThe Kaiser Healthy Aging and Diverse Life Experiences Study (KHANDLE) is a cohort of community‐dwelling Kaiser Permanente members residing in Northern California (Asians (26%), Blacks (29%), Latinos (20%) and Whites (24%)) who completed a multiphasic health checkup (MHC) from 1977‐1985 (n=1,207; mean age=37.6). KHANDLE aims to evaluate how lifecourse factors influence late‐life brain health and cognitive decline and may impact race/ethnic disparities. Using linear regression, we examined the association between late‐life cognition and early/midlife hypertension, hyperlipidemia and overweight/obesity collected at MHC. Executive function, semantic memory and verbal episodic memory measured using the Spanish and English Neuropsychological Assessment Scales (SENAS) were z‐standardized and combined for a composite measure of overall cognition. We tested for effect modification by race/ethnicity. Models controlled for age at KHANDLE, age at MHC, gender, and education.ResultsAt KHANDLE baseline, mean age was 75.4(6.7). At MHC, 46% of participants were ages 26‐35, 47% ages 36‐49 and 7% ages 50‐65. Prevalence of 2+ CVR was highest in Blacks (24%), followed by Latinos (24%), Asians (15%), and Whites (13%). Across race/ethnicity, having 2+ risk factors was associated with lower cognition in all domains: Overall cognition β=‐0.35 (‐0.47, ‐0.23). Having hypertension, hyperlipidemia or being overweight/obese was associated with worse cognition in all race/ethnic groups and across all cognitive domains (see table). Effect estimates varied by race/ethnicity, but interactions were not statistically significant: Blacks with hypertension (n=108) had lower late‐life cognition than other groups, especially for semantic memory and verbal episodic memory; Latinos with hyperlipidemia (n=49) had worse verbal memory than other groups; whites who were overweight/obese (n=84) had lower late‐life cognition across all domains, while Asians who were overweight/obese (n=50) had better late‐life cognition than non‐Asian participants who were overweight/obese.ConclusionsEarly/midlife cardiovascular risk factors are associated with lower late‐life cognition in all race/ethnic groups. The association between specific cardiovascular risk factors and late‐life cognition may vary by race/ethnicity, but differences were not significant.
Transcriptomic profiles underlying functional brain networks at different stages of Alzheimer’s disease
Authors: Yu Meichen , Nho Kwangsik , Risacher Shannon L. , Chumin Evgeny J. , West John D. , Tharp Matt , Zhu Jian , Wen Qiuting , Eastman Bobi , Shen Li , Apostolova Liana G. , Wu Yu‐Chien , Sporns Olaf , Saykin Andrew J. 
Published: December 2020

AbstractBackgroundSpecific functional network connectivity patterns have been shown at different stages along the Alzheimer’s disease (AD) continuum, but the contribution of regional gene expression to molecular mechanisms remains unknown.MethodWe used resting‐state functional MRI to construct functional brain networks in 47 cognitively normal (CN), 46 subjective cognitive decline (SCD), 34 mild cognitive impairment (MCI) and 22 AD participants. Regional gene expression profiles for 20736 protein‐coding genes were derived from brain‐wide microarray‐based transcriptome data from the Allen Human Brain Atlas. We performed one hypothesis‐driven (using pre‐selected AD susceptibility genes) and two data‐driven analyses (using all 20736 genes) to uncover the spatial associations between brain‐wide gene expression levels and connectivity strength (gene‐to‐connectivity associations). In the hypothesis‐driven analysis, we computed the spatial gene‐to‐connectivity associations for 51 AD susceptibility genes selected from large‐scale GWAS for the four clinical groups, separately. In a data‐driven analysis, we determined the gene‐to‐connectivity associations for average gene expression levels of co‐expressed gene modules in the gene co‐expression network. We also performed gene‐set enrichment analysis (GSEA) to identify biochemical pathways associated with the connectivity patterns in AD (1000 permutations; PFDR < 0.05; gene sets from the Gene Ontology). Finally, we analyzed commonalities among the most relevant genes of the identified pathways.ResultWe identified 15 AD susceptibility genes showing significant gene‐to‐connectivity associations after multiple testing adjustment (PFDR < 0.05). In particular, ECHDC3 and HS3ST1 showed the strongest positive and negative gene‐to‐connectivity associations, respectively, and the strength of the correlations increased as a function of disease stage (CN < SCD < MCI < AD). In addition, two of five gene co‐expression modules showed consistently significant gene‐to‐connectivity associations across the four clinical groups. GSEA identified 31 positively enriched pathways including cellular response to metal ion and fatty acid binding, and 11 negatively enriched pathways including enzyme activity and cellular metabolism.ConclusionOur findings may open novel avenues for improving the interpretation of genetic and imaging biomarkers, for facilitating the detectability of AD trajectories, and for developing effective therapeutic strategies at earlier stages of the disease spectrum when connectivity changes may be among the earliest features.
Dementia knowledge and associated demographic factors within a registry sample
Authors: Reynolds Gretchen O , Manning Lyssa K , Kirn Dylan , Burke Orett , Klein Hannah , Rentz Dorene , Sperling Reisa A. , Marshall Gad A , Amariglio Rebecca 
Published: December 2020

AbstractBackgroundResearch on Alzheimer’s disease (AD) and related dementias is increasingly focused on prevention and identification of risk factors. In order to effectively disseminate knowledge about dementia risk, there is need to understand gaps in dementia knowledge (Carpenter et al., 2011, Cations et al., 2018). For example, education level, among other factors, may be associated with reduced knowledge about AD, which could impact engagement in early prevention strategies (Ayalon & Arean, 2004). We explored dementia knowledge and demographic variables in a community‐based registry sample to inform approaches to psychoeducation and intervention.MethodWe administered surveys via REDCap to participants enrolled in an online registry. Surveys included measures of dementia knowledge (subset of 13 questions from the Dementia Knowledge Assessment Scale (DKAS)), personality (Ten‐Item Personality Inventory), and demographic variables. Response rate was 42%. Participants were 292 clinically normal adults (mean age=67.4 (range: 50‐87); 65% women; 98% non‐Hispanic or Latino; 94% Caucasian; 81% with a bachelor’s degree or higher).ResultMost participants (77%) reported knowing “some” to “a good amount” about dementia, learned primarily via family/friends (27%), doctors (21%), and the internet (22%). Mean dementia knowledge on the DKAS was 14.4 (range=1‐26, out of 26 possible points). Dementia knowledge was weakly associated with age (r=‐.12, p=.045), with younger individuals showing higher knowledge. Controlling for age, self‐reported dementia knowledge correlated with objective dementia knowledge on the DKAS (r=.46, p<.01). Also controlling for age, dementia knowledge was higher among individuals with more education (F(1, 287)=8.6, p=.004) and among women (F(1, 285)=5.9, p=.016). Dementia knowledge was not associated with aspects of personality (ps>.08).ConclusionDementia knowledge was higher among younger individuals, as well as those with more education and among women, but did not relate to personality. Self‐reported dementia knowledge correlated with objective dementia knowledge, suggesting that participants accurately judged their own knowledge. Future work should examine these questions within a more diverse registry sample. Findings underscore the value of registries to examine dementia knowledge and inform dissemination and intervention strategies. By increasing psychoeducation about dementia among adults with lower baseline knowledge, we may facilitate early engagement in preventative strategies to reduce dementia risk.
Racial/ethnic differences in the association of high school quality with later life cognitive function
Authors: Seblova Dominika 
Published: December 2020

AbstractBackgroundLonger education predicts better cognitive health, but it is unclear whether other attributes of schooling matter, or whether educational opportunities confer equal benefits across our society. We examined racial/ethnic differences in the association of high school quality with later life cognition among a unique cohort of older adults followed since high school.MethodIn 1960, about 5% of US high schools participated in Project Talent (PT). PT measured demographics and aptitude in students and gathered objective information about school characteristics. In 2018‐2019, a total of 2,353 PT participants (mean age=74.6) responded to a telephone interview, which included neuropsychological tests. Language ability was measured with animal (semantic) and letter F (phonemic) fluency. Memory was measured with the CERAD learning list and delayed recall savings. A school quality factor score, capturing term length, class size, and teacher qualifications, was used as a predictor of individual test scores. We examined differences in the association between school quality and cognitive function by self‐reported race/ethnicity. For each outcome, we estimated two linear regression models. We first estimated the main effects of school quality and race/ethnicity, adjusting for 1960 cognitive aptitude, sex/gender, age, and a composite measure of parental socioeconomic status, then we added an interaction term for school quality and race/ethnicity.ResultRespondents were mostly non‐Hispanic White (76%), 10% non‐Hispanic Black, 4% Hispanic (of any race) and 9% self‐identified as Asian, Pacific Islander, Middle Eastern/North African, American Indian/Alaska Native, or more than one race. School quality was highest for Hispanic respondents and lowest for Blacks. Higher school quality was associated with higher cognitive scores 58 years later, reaching statistical significance for CERAD learning (0.05 SD; 95%CI: 0.01;0.09) and letter fluency 0.07 SD (95%CI 0.03;0.1). Whites, Hispanics, and other racial/ethnic groups benefited more from higher school quality compared to Blacks, and this was reliably different for phonemic fluency.ConclusionAttending higher quality high schools was associated with better scores on neurocognitive tests 58 years later. Future work will examine the structural and social inequalities to address why non‐Hispanic Black students had lower cognitive benefits from higher school quality than other racial/ethnic groups.
Practice effect of repeated cognitive tests among older adults: Associations with brain amyloid status and other influencing factors
Authors: Zheng Bang , Udeh‐Momoh Chinedu T. , Price Geraint J , Watermeyer Tam J. , Jager Celeste A. , Ford Jamie , Robb Catherine , Giannakopoulou Parthenia , Fogle Michael , Saad Ziad , Ahmadi‐Abhari Sara , Ritchie Craig W. , Baker David , Novak Gerald P. , Middleton Lefkos T. 
Published: December 2020

AbstractBackgroundPractice effects (PE), after repeated cognitive measurements, may mask cognitive decline and remain a major issue in clinical and research settings. However, an attenuated practice effect may indicate cognitive decline or the presence of brain pathologies. Exploring factors that influence PE can inform strategies to distinguish true signal from bias in future research. This study aimed to evaluate practice effects on the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) scale, and their associations with brain amyloid status in a cohort of older adults enrolled in the Cognitive Health in Ageing Register: Investigational, Observational, and Trial Studies: Prospective Readiness cOhort Study (CHARIOT‐PRO) Sub‐study.Method502 cognitively healthy participants aged 60‐85 years were assessed with RBANS in both screening and baseline clinic visits (median time gap of 3.5 months). We assessed the reliability of the RBANS scale and tested PE based on differences between test and retest scores in total scale and domain‐specific indices. Multiple linear regressions were used to examine factors influencing PE, after adjusting for age, sex, educational attainment, and APOE‐ε4 carriage. PE and the initial RBANS score were also examined as predictors for amyloid positivity status based on defined thresholds, using logistic regression.ResultThe internal consistency (Cronbach's α=0.64) and test‐retest reliability (r=0.79) of RBANS were good. Participants’ Total Scale, Immediate Memory and Delayed Memory indices were significantly higher in the second test than in the initial test (d=3.8, 7.6 and 3.2, P<0.001). On the Immediate Memory index, the PE was significantly lower in the amyloid positive group than the amyloid negative group (d=6.5 vs 8.6, P=0.028). Older participants (≥70 years), women, non‐APOE‐ε4 carriers, and those with worse initial RBANS test performance had larger PE. In addition, worse performance and lower practice effects in immediate or delayed memory index were independent predictors for amyloid positivity (OR=0.97, P<0.05).ConclusionSignificant practice effects on RBANS total scale and memory indices were influenced by age, sex, APOE‐ε4, initial RBANS scores and amyloid status. The association with amyloid suggests that practice effects are not simply a source of measurement error but may be informative with regard to underlying neuropathology.
In‐out‐test and inverse translational medicine: When a new clinical paradigm is needed to find new biomarker perspectives
Authors: Torrealba Eduardo , Garcia‐Morales Pilar , Rodriguez‐Esparragon Francisco 
Published: December 2020

AbstractBackgroundPROA project is based in the Neurology Service and the Investigation Unit at the Hospital Dr. Negrin (Canary Islands, Spain). PROA aims to find new ways to a better understanding of cognitive and biological mechanisms of normal aging and Alzheimer's disease (AD). This study shows previous, preliminary and ongoing PROA project data about the relationship between clinical assessment and biomarkers in Alzheimer’s disease research. It is considered the contribution of In‐out test, a paradigm hypothesized to avoid reliance on executive function, which may compensate damaged memory networks. Unlike other tests using the hippocampal amnesia paradigm, that assess memory after effective encoding of information, the In‐out‐test provokes an interference during encoding by means of a simultaneous executive task. According to this model the memory deficit in prodromal AD can be unmasked when those compensatory networks are saturated by an executive activity without being able to compensate the already damaged mnemonic activity.MethodNeuropsychological assessment: Neuropsychological battery: episodic (Free and cued Selective Reminding Test‐ FCSRT), shot‐term, visual memory, visuospacial and constructive praxis; executive functions; Daily living and instrumental activities. In‐out‐test: Assesses episodic memory after the patient performs a categorization task and memorizes 6 words simultaneously. The time taken to complete this test was 5 to 12 minutes.ResultCross‐sectional study: ICC (Intraclass correlation) between the In‐out‐test and FCSRT r= 0.87 (p=0.001). ICC between the In‐out‐test and Aβ42 and P‐tau/Aβ42 for controls: 0.73 and 0.75 respectively; P‐tau for MCI: 0.77 and total sample: 0.70; Aβ42 for dementia: 0.71. All ICC measures between FCSRT and biomarkers were ≤ 0.264. Sensitivity: 0.93; specificity: 0.77. Predictive value for In‐out‐tet, Positive:0.89; negative: 0.83. Conversion study: Agreement (Kappa): In‐out‐test: 0.67/0.61 (memory/learning); FCSRT: 0.57; P‐tau/Aβ42: 0.126. P‐tau(50ng/ml): 0.40. Aβ42 (500 ng/ml): 0.07ConclusionCompensatory mechanisms in prodromal AD might be a confounding factor in the early detection by classical hippocampal amnesia paradigm and even by csf biomarkers. In‐out‐test may play a roll unmasking the memory deficit in the early stages of AD. In orfer to find new reliable biomarkers for aging and AD, PROA project will focused on new targets such as oxidative stress, phosphorilation, microbiota and telomers.