bluuebunny/crossref_metadata_2025_split huggingface dataset:
Associations between plasma p‐tau217, in vivo brain pathology and cognition in individuals with autosomal‐dominant Alzheimer’s disease: Findings from the Colombia‐Boston (COLBOS) biomarker study
Authors: Aguillon David , Vila‐Castelar Clara , Chen Yinghua , Su Yi , Chen Kewei , Hansson Oskar , Dage Jeffrey L. , Janelidze Shorena , Zetterberg Henrik , Baena Ana Y. , Gómez‐Henck Clara , Fox‐Fuller Joshua T. , Sanchez Justin S. , Sperling Reisa A. , Johnson Keith A. , Blennow Kaj , Reiman Eric M. , Lopera Francisco , Quiroz Yakeel T. 
Published: December 2021

AbstractBackgroundDiagnostic methods available for in‐vivo diagnosis of Alzheimer's disease (AD) are expensive and invasive. Interest in plasma P‐tau217 has recently grown as it seems to have higher diagnostic accuracy for clinical AD, compared to other blood biomarkers in preclinical stages. We recently showed that carriers of autosomal dominant AD due to the PSEN1‐E280A mutation had increased plasma P‐tau217 levels, approximately 20 years prior their estimated onset of mild cognitive impairment. Here, we examined whether baseline levels of plasma P‐tau217 may predict subsequent levels of in vivo cortical amyloid‐β, regional tau pathology, and memory performance in PSEN1‐E280A carriers and non‐carriers.
MethodsA total of 24 PSEN1‐E280A carriers (mean age = 31.13 ± 6.81 years), including 18 cognitively‐unimpaired and 6 with MCI, and 20 age‐matched non‐carriers (mean age = 27.55 ± 6.99) from the Colombia‐Boston (COLBOS) biomarker study were included. Participants underwent blood sampling at baseline and PiB‐PET, Flortaucipir‐PET, and memory testing after 8.95±4.19 years of follow‐up. Plasma P‐tau217 concentrations were measured using a highly sensitive immunoassay. Linear regressions were used to examine associations of baseline P‐tau217 levels with subsequent in vivo amyloid, tau levels in the brain and memory scores each, with age, sex, carrier group membership and time from baseline to follow‐up examinations as covariates.ResultsCompared to non‐carriers, mutation carriers had higher P‐tau217 levels (carriers: 5.27±4.69, non‐carriers: 2.53±1.39; p=0.016), greater regional tau (e.g. entorhinal cortex, inferior temporal tau; p <0.0001) and cortical amyloid (p <0.0001), and lower memory scores (e.g. CERAD Word List Recall; p=0.001). Higher baseline P‐tau217 levels were associated with subsequent elevations in in vivo amyloid and tau pathology and memory decline in carriers (Figure 1).ConclusionFindings suggest that baseline levels of plasma P‐tau217 may predict subsequent levels of in vivo amyloid and tau burden, as well as memory decline in PSEN1‐E280A carriers and non‐carriers. These findings provide further support for plasma P‐tau217 as a potential non‐invasive diagnostic and prognostic biomarker of AD, which could be useful in clinical practice and trials.
Mapping the human brain metabolome and influences of gut microbiome
Authors: Batra Richa , Heinken Almut , Karu Naama , Arnold Matthias , Kastenmüller Gabi , Hankemeier Thomas , Bennett David A. , Knight Rob , Krumsiek Jan , Thiele Ines , Kaddurah‐Daouk Rima F. 
Published: December 2021

AbstractBackgroundThere is compelling evidence implying critical role of gut‐brain axis in neuropsychiatric diseases including Alzheimer’s disease (AD). Consequently, microbially‐derived metabolites, e.g., secondary bile acids, have been shown to be altered in blood, faecal and brain tissues of AD patients. The presence of these microbially‐derived products in brain suggests that gut metabolites can cross the blood brain barrier and modify brain function. Yet it remains challenging to disentangle human and microbial contributions to the brain metabolome and to link microbial metabolites back to species of origin.MethodBased on a literature review effort, a database of over 500 metabolites was manually curated, including microbial metabolites of endogenous and exogenous compounds, as well as their human‐biotransformed products, and health‐reporting compounds which are related to CNS diseases. Human brains (n=514; dorsolateral prefrontal cortex) from the ROSMAP cohort were profiled on the Metabolon TD4 non‐targeted metabolomics platform which measured 1,055 metabolites. Here, by combining the curated database and the metabolic profiling data from the ROSMAP brains, we built a new database of metabolites found in the human brain. In addition, metabolites from both efforts were mapped to the global human reconstruction, Recon3D, and to a resource of 7,206 human microbial reconstructions, AGORA2.Result667 (63.2%) metabolites were retained after filtering out metabolites for high missing values. Of these metabolites, 254 were mapped onto genome‐scale metabolic reconstructions (Recon3D and AGORA2) with 67 being found only in human, 13 only in microbes, and 174 in both human and microbes. 12 additional metabolites were of microbial or mainly microbial origin according to our in‐house database. Many of these (13+12) metabolites were associated (adjusted p‐value <0.05) with AD clinical phenotypes including clinical diagnosis at time of death, AD pathology, and cognitive decline.ConclusionWe developed a database of the human brain metabolome with comprehensive annotations of human and microbial metabolic networks, ranked in order of importance. The human brain database will be a valuable tool for researchers to define metabolic aberrances in Alzheimer’s disease and the contribution of the gut microbiome, genome, and life style influences on brain metabolic states in health and disease.
Effects of dancing on cognition and mobility in Spanish‐speaking older Latinos: findings from the BAILA trial
Authors: Aguiñaga Susan , Kaushal Navin , Wilson Robert S , Marquez David X 
Published: December 2021

AbstractBackgroundDespite literature showing the benefits of regular physical activity (PA), 1,2 older Latinos engage in low levels of PA3 putting them at high risk for mobility disability5 and cognitive impairment.2 Engaging Latinos in culturally responsive PA programs is important to improve cognition and physical function. The purpose of the present study was to examine the effect of a 4‐month BAILAMOS™ Latin dance intervention, followed by a 4‐month maintenance program on cognition and mobility in community dwelling older Latinos.MethodSpanish‐speaking older Latinos were randomized to the dance program (n=167) or health education condition (n=166). Participants completed neuropsychological tests that assessed working memory (WM), executive function, and episodic memory and completed a 400‐meter walk test at baseline, 4‐months, and 8‐months post‐intervention. Repeated analyses of covariance were conducted to test change in the outcomes at 4‐months and 8‐months post‐intervention. Significant findings found at the multivariate level were followed by reporting results from the univariate tests.ResultA significant difference in WM was found between the two groups [Wilk’s λ = .98 F 2,329 = 3.97, p = 0.034]. Follow‐up univariate tests found that the two groups were not significantly different at 4‐months, [F 1,329 = 3.74, p = 0.235, (d = .13)], but the dance group demonstrated a significant improvement in WM at 8‐months, [F 1,329 = 6.92, p = 0.017, (d = .20)]. No significant differences were found for executive function or episodic memory. For the 400‐meter walk test, findings show a significant difference between the two groups [Wilk’s λ = .98, F 2,329 = 4.37, p = 0.022]. Univariate tests revealed that the two groups were not significantly different at 4‐months, but were significantly different at 8‐months, [F 1,329 = 7.24, p = 0.013], such that the dance group had better mobility than the health education group, (d = ‐.46).ConclusionFindings indicate that participants who received the 4‐month maintenance dance program led to changes in WM and mobility. This study highlights the cognitive and physical implications and the importance of creating sustainable community‐based PA programs. Funding: National Institute of Nursing Research: R01NR013151.
Does higher educational attainment influence functional capabilities among African Americans with Alzheimer’s disease?
Authors: Lacroix Faina C , Adams Larry D. , Inciute Jovita D. , Welch Jacob , Starks Takiyah D. , Laux Renee A. , Byrd Goldie S. , Haines Jonathan L. , Beecham Gary W. , Cuccaro Michael L. , Vance Jeffery M. , Pericak‐Vance Margaret A. , Rajabli Farid 
Published: December 2021

AbstractBackgroundA recent study of educational attainment (EA) in African Americans (AA) demonstrated that it is associated with a decreased risk of AD, as previously described in the Non‐Hispanic White population. Several studies have also suggested that EA is a proxy for the concept of cognitive reserve (CR) or the capacity of the brains of some individuals to compensate clinically for the neurodegenerative processes of AD. If true, then EA should also be associated with other aspects of AD, including functional impairment, often measured using the Clinical Dementia Rating scale (CDR). The aim of this study is to test the hypothesis that higher EA is associated with decreased functional impairment in AA.MethodsParticipants consisted of 158 AA AD cases with known years of completed education, ascertained for a genetics study of AD. Education levels were stratified into three categories:<8 years, 9‐12 years, >12 years. We used a regression model to test the association between years of education and functional impairment (composite score) with the age at onset and sex as covariates. Using the non‐memory components of the CDR: Judgment and Problem solving, Home and Hobbies, Community Involvement, and Personal Care, we formulated a composite score of 12 totaling the individual score of the 4 components. A composite score of 0 is no functional impairment and 12 equals severe functional impairment.ResultsThe dataset was 77.2% female with a mean age of exam of 78.8 years and a mean CDR functional composite score of 1.97 and a mean educational attainment of 11.3 years. Our results showed a significant association between education and the composite score ( ). An increase in the years of education was negatively correlated with functional impairment.ConclusionOur data support the hypothesis that higher educational attainment is associated with reduced functional impairment. These results extend and support the concept that EA is a measure of CR in AA, extending the role of CR and EA to functional abilities. Further studies on the mechanism by which EA is protective is needed. In addition, our results suggest that EA should be considered when evaluating functional abilities in individuals thought to have AD.
The relationship between subjective cognitive decline and demographic characteristics is moderated by study setting: Findings from the SCD‐I Item Analysis Working Group
Authors: Sikkes Sietske A.M. , Dubbelman Mark A. , Tommet Douglas , Jones Richard N , Crane Paul K. , Rabin Laura ,   SCD‐I Working Group, SCD‐PIA
Published: December 2021

AbstractBackgroundSubjective Cognitive Decline (SCD) in the absence of objective cognitive impairment has been linked to progression to Alzheimer’s Disease and Related Disorders dementia. Demographic characteristics might bias the measurement of SCD, but it remains unclear how these characteristics relate to SCD. As part of the international SCD‐I item analysis working group, we previously harmonized item‐level SCD questionnaires from cognitive aging studies in North America and Europe into a subjective cognition factor (SCF) score. Here, we aimed to investigate the relationship between SCF and demographic characteristics, as well as the potential moderating role of community‐based versus memory specialty clinic settings.MethodIn this cross‐sectional study, data from 13 international aging studies was included (N=4,979 cognitively normal participants, mean age 75±8, 61% female). Over 600 different SCD questionnaire items were harmonized into the SCF score using item response theory modeling. A series of univariate multilevel linear regression analyses were performed to investigate the relationship between age, gender, education and SCF, with setting (community‐based versus memory clinic) included as fixed factor.ResultAfter multilevel adjustment for study clustering, lower SCF, indicating worse subjective cognitive functioning, was associated with older age, such that a 10 year difference in age was associated with a 0.05 standard deviation lower SCF (p=.04, see Table 1). Females reported better subjective cognitive functioning (B=.07, p<.01). No association with education was found across settings. When stratified, the relationships between SCF, gender and age were apparent in the community‐based but not the memory clinic‐based settings (see Table 1).ConclusionThis is the first study using the harmonized SCF score to study the relationship between SCD and demographic characteristics. This SCD metric applicable across studies could serve as a major facilitator in studying SCD. We found men and older individuals to report slightly lower levels of subjective cognitive functioning, driven by the community‐based setting. These findings suggest that relationships between age and SCD may be different among people motivated to seek medical attention for their cognition compared to unselected individuals in the community.
A comparison of multiple platforms for quantifying ATN values in cerebrospinal fluid
Authors: Ramirez Christopher E. , Trombetta Bianca A. , Celia Amanda M. , LaCasse Kathryn , Mattingly Zoe A. , Salloum Lauren , Orusakwe Amanze , Esquivel Rianne N. , Carlyle Becky C. , Kivisäkk Pia , Arnold Steven E. 
Published: December 2021

AbstractBackgroundThe ATN framework is used to help categorize research subjects as being on the Alzheimer’s disease (AD) spectrum. Analytes commonly used in biofluids to determine ATN status were measured across three platforms to examine the reliability of each technology and inter‐platform variability.MethodCerebrospinal fluid (CSF) samples were obtained from 734 patients undergoing diagnostic lumbar punctures at the MGH Neurology Department. Amyloid β 1–40 (Aβ40), Aβ42, total Tau (tTau), and phosphorylated Tau 181 (pTau 181) were measured in all subjects using EuroImmun ELISA kits on a TECAN FreedomEVO liquid handler. 423 of the subjects also had all four biomarkers measured on a Fujirebio Lumipulse G1200 instrument and 164 had levels of Aβ40 and Aβ42 measured on the Quanterix HD‐X platform. 302 of the subjects had Aβ42, tTau, and pTau 181 quantified by Athena ADmark assays as part of their clinical evaluation. Coefficient of Variations (CVs) were calculated, and data was correlated between platforms to determine inter‐platform variability.ResultThe average CV for each analyte was <5% for samples analyzed on the EuroImmun/TECAN platform and <10% on the Fujirebio Lumipulse and Quanterix HD‐X. CVs >20% were not seen in subjects with detectable analyte levels on the EuroImmun/TECAN or Quanterix platforms and the incidence was <5% on the Fujirebio platform. Tight correlations were observed between levels measured on the EuroImmun/TECAN and Fujirebio platforms (R2>0.8), while lower correlations were observed between the EuroImmun/TECAN and Quanterix platforms (R2=0.4‐0.5 for Aβ40 and Aβ42). The lowest correlation was observed comparing Aβ42 analyzed using EuroImmun/TECAN and Athena ADmark (). ICC values were >0.7 for all analytes compared between EuroImmun/TECAN and Fujirebio platforms.ConclusionWe observed good reliability using all three platforms. to conserve sample. ATN values showed strong correlations between the EuroImmun/TECAN and the Fujirebio platforms and produce . The poor correlation for the Athena ADmark Aβ42 is likely a result of poor control of pre analytical factors in the samples sent for clinical testing and highlights the importance for proper sample handling.
Structural and functional connectivity uniquely contribute to explained variance in episodic memory performance in cognitively normal older adults
Authors: Alm Kylie H. , Soldan Anja , Pettigrew Corinne , Faria Andreia , Hou Xirui , Lu Hanzhang , Mori Susumu , Albert Marilyn S. , Bakker Arnold 
Published: December 2021

AbstractBackgroundGiven mounting evidence that AD‐related neuropathological changes may be present in cognitively normal individuals, there is a need to examine brain biomarkers related to variability in cognition that may precede cognitive decline. Although prior studies demonstrate age‐related changes in structural connectivity (SC) and functional connectivity (FC) separately (Contreras et al., 2015), few have adopted a multimodal approach to test the potential interplay between SC and FC, and their relative associations with cognition. Here, we examined the independent contributions of SC and FC to individual differences in episodic memory performance in cognitively normal older adults.MethodThis cross‐sectional study included 107 cognitively normal participants from the BIOCARD study. SC was indexed using radial diffusivity (RD) and mean diffusivity (MD) of two limbic white matter tracts (fornix and hippocampal cingulum), as measured by diffusion‐weighted MRI. FC within five large‐scale brain networks (control, default, limbic, dorsal attention, and salience/ventral attention) was derived using resting state fMRI. Hierarchical linear regression was utilized to directly compare the relative contributions of SC and FC to individual variability in a composite delayed episodic memory score, while also accounting for age, sex, cerebrospinal fluid (CSF) Aß42 and total tau, and gray matter volumes of the entorhinal cortex and hippocampus.ResultsWhen all five FC networks were included in the regression, only the salience network emerged as a significant FC predictor. Therefore, we performed a follow‐up analysis with salience network connectivity as the only FC measure of interest. In this model, the addition of both SC and FC measures (but not CSF or gray matter volumes) significantly increased the proportion of explained variance in memory performance, and all three measures (fornix/hippocampal cingulum microstructure, and salience network connectivity) were significant independent predictors of memory performance.ConclusionThese findings demonstrate that both connectivity modalities make unique contributions to episodic memory performance, but CSF and gray mater volumes do not. Furthermore, the highest proportion of explained variance was achieved when both modalities were included in the model, suggesting that the combination of SC and FC markers best accounts for individual variability in episodic memory in cognitively normal older adults.
Using cerebrospinal fluid ATN quantification to classify research subjects in a diverse clinical population
Authors: LaCasse Kathryn , Trombetta Bianca A. , El‐Mufti Leena , Ramirez Christopher E. , Mattingly Zoe A , Celia Amanda M. , Salloum Lauren , Carlyle Becky C. , Kivisäkk Pia , Wills Anne‐Marie , Arnold Steven E. 
Published: December 2021

AbstractBackgroundThe ATN Framework was proposed to better classify subjects on the Alzheimer’s Disease (AD) spectrum for research purposes. The role of the MassGeneral Institute for Neurodegenerative Disease (MIND) Tissue bank is to collect cerebrospinal fluid (CSF), plasma, and associated clinical data from a diverse neurological subject population. Ab40, Ab42, p‐tau 181, and t‐tau were quantified in CSF samples from the MIND Bank and classified according to the ATN framework to assess the utility of this research framework in a clinical trial relevant, non‐cohort setting.Method750 CSF samples were collected from clinically indicated lumbar punctures at the Massachusetts General Hospital Outpatient and Inpatient Neurology Services. The CSF samples were analyzed using Eurolmmun ELISA assays on a semi‐automated TECAN FreedomEVO liquid handler to obtain ATN values. To optimize sensitivity and specificity we plotted these value across varying thresholds, and selected the value at which both were maximized. Assessment of cognitive impairment and neurological diagnosis was performed by chart review by an experienced neurologist.ResultAfter sliding threshold analysis of clear cognitively unimpaired versus AD‐Dementia cases, a threshold value for Ab42/40 Ratio (0.082, 92% sensitivity, 91% specificity), pTau (41.8 pg/mL, 91% sensitivity, 91% specificity), and tTau (280 pg/mL, 88% sensitivity, 88% specificity) was determined. 25% of the MIND bank was classified as likely AD from chart review and a similar proportion was biofluid A+T+N+. The overlap of these two subgroups was extensive but not complete. Out of the 188 A+T+N+ subjects, 152 presented clinically with a form of AD, 6 had other neurodegenerative diseases, 23 had other forms of cognitive impairment, and 7 were cognitively unimpaired. 8 of the 419 A‐T‐N‐ subjects had a clinical diagnosis of AD or mixed AD.ConclusionThe ATN framework can be used to provide an extra level of certainty with regards to diagnosis of likely AD in a clinical trial relevant subject population. Even in this population with clinical indication for LP, there is a small number of resilient cognitively unimpaired individuals that have AD positive biomarkers but no cognitive impairment.
Apathy may be a key link between depressive symptoms and subjective cognitive decline
Authors: Joyce Jillian L , Chapman Silvia , Barker Megan S , Sunderaraman Preeti , Rizer Sandra , Huey Edward D. , Kreisl William Charles , Cosentino Stephanie 
Published: December 2021

AbstractBackgroundSubjective Cognitive Decline (SCD), a potential marker of pre‐clinical AD, is frequently linked to mood disturbances, such as depression and apathy. These associations are thought to hinder the utility of SCD as a predictor of impending disease. However, recent evidence suggests that depression and apathy are separate constructs that may pose differential risk for cognitive impairment and neurodegeneration. Further, some studies have reported apathy to be a more sensitive predictor of cognitive decline than depression. Therefore, understanding the associations between SCD and mood will help refine SCD’s utility as a marker of pre‐clinical AD. This study examines those associations with particular focus on whether apathy mediates the association between depressive symptoms and SCD.Method151 cognitively normal older adults (68% female, mean age 73±7) were assessed for level of SCD, apathy, and depressive symptoms using a 20‐item age‐anchored SCD questionnaire (i.e., “in comparison to others your age”), the Apathy Evaluation Scale and the Geriatric Depression Scale (GDS), respectively. Regression analyses examined the main effects of apathy and depressive symptoms on SCD, and apathy as a mediator between SCD and depressive symptoms. Regression analyses were also conducted after removing three GDS items previously shown to form an apathy factor.ResultApathy (b=.84, p=.001) and depressive symptoms (b=4.57, p=.002) independently predicted SCD. In the mediation model, depressive symptoms predicted apathy (b=2.91, p<.001) but not SCD (b=2.14, p=.183). Apathy mediated the relationship between depressive symptoms and SCD (Indirect effect: b=2.44 SE=.80, CI(1.07, 4.30), accounting for 53% of the total effect. Apathy still remained a significant mediator even after eliminating the apathy‐related items from the GDS (Indirect effect: b=1.52 SE=.65, CI(.40, 2.92)), accounting for 40% of the total effect.ConclusionApathy mediated the relationship between depressive symptoms and memory complaints, even when the GDS only included the dysphoric and anxious elements of depression. These results underscore the relevance of apathy in preclinical stages of disease and is in line with previous studies indicating apathy’s unique association with cognitive impairment and neurodegeneration. Longitudinal studies are required to further disentangle the temporality and potential additive risk for dementia of SCD and apathy.