bluuebunny/crossref_metadata_2025_split huggingface dataset:
Developing a novel peptide aptamer‐based treatment of Alzheimer’s disease
Authors: Ali Tahir , Klein Antonia N. , Vu Alex , Gilch Sabine 
Published: December 2021

AbstractBackgroundAlzheimer’s disease (AD) is a major cause of dementia and age‐related neurodegenerative disease with no current treatment. Pathologically, AD is characterized primarily by accumulation of amyloid‐β (Aβ) in the brain. The interaction of Aβ‐oligomers (Aβo) with the cellular prion protein (PrPC) subsequently mediated AD pathologies. The interference with Aβo‐PrPC interaction is a valuable strategy for developing therapeutics for AD. Previously, we developed peptide aptamers (PAs) binding to the PrPC, partially covering the binding site of Aβo . In this study, we aimed to investigate the PAs effects on preventing Aβo‐PrPC interaction and toxicity in vitro and pathologies in AD models.MethodWild type mouse neuroblastoma N2a cells (overexpressing mouse PrP) were treated with Aβ (1 mM) and PAs (10 µg/ml), and after 24 hr performed the MTT assay. Following these in vitro experiments, we carried out in vivo experiments using transgenic 5xFAD (expressing human APP and PSEN1 transgenes harboring in total 5 mutations associated with familial AD) mice. The 5xFAD mice were treated with PAs at a 14.4 ug /day dosage for 6 weeks by intraventricular infusion using Alzet® osmotic pumps. After completion of treatment, fear conditioning test (FCT) was performed for consolidated leaning and memory functions of the 5xFAD mice.ResultThe MTT results indicated that PA treatment significantly reduced Aβo‐induced toxicity. Overall, our in vitro results indicated that PAs reduced Aβ‐induced neurotoxicity. In the FCT, we observed that PAs increased the time of freezing percentage as comparted to the non‐treated 5xFAD mice. The FCT results represented that PAs significantly improved consolidated learning and memory functions of 5xFAD mice as compared to the non‐treated 5xFAD mice.ConclusionOur results demonstrate that treatment with PAs targeting Aβo‐PrPC interaction would be valuable and novel strategy to treat AD.
Sleep disruption and disorders in former college and professional American football players
Authors: Alosco Michael L. , Adler Charles , Dodick David W. , Balcer Laura , Bernick Charles B. , Palmisano Joseph , Tripodis Yorghos , Cummings Jeffrey L. , Reiman Eric M. , Shenton Martha E. , Stern Robert A. , Banks Sarah J. 
Published: December 2021

AbstractBackgroundLittle is known about sleep in those with a history of contact sports, who are at increased risk for neurodegenerative disease(s). Sleep disruption and disorders are increasingly recognized as having a bidirectional relationship with Alzheimer’s disease neuropathology. Here, we investigated self‐reported sleep disruption and disorders in male former college and professional American football players.Method116 former National Football League (NFL) players, 60 former college football players, and 60 asymptomatic men without a history of traumatic brain injury or repetitive head impacts (controls), all between 45‐74 years, completed the Mayo Sleep Questionnaire (MSQ) which includes the Epworth Sleepiness Scale (ESS). Former American football players were enrolled across the spectrum of symptom severity (asymptomatic to mild dementia). Using binary logistic regression or analysis of covariance, comparisons (controlling for age, racial identity, body mass index, APOE e4 status) on each of the MSQ items and the ESS were made between each of the study groups.ResultCompared to controls, former NFL players were more likely to restless legs (OR = 7.32, 95% CI = 1.63‐32.97*), sleepwalking (OR = 8.65, 95% CI = 1.08‐69.22*), observed apnea (OR = 2.25, 95% CI = 1.04‐4.85*), lower alertness levels (marginal mean diff. = 0.90**) and had higher ESS (marginal mean diff. = 2.37**). Former college football players reported greater sleep disturbances compared with controls: restless legs (OR = 10.82, 95% CI = 1.86‐62.89**), sleepwalking (OR = 10.45, 95% CI = 1.12‐97.58*), alertness levels (marginal mean diff. = 1.48**) and ESS (marginal mean diff. = 2.76*). There were no college vs control differences for observed apnea. There were no differences between former NFL players and former college football players on any sleep metric. **p<.005, *p<.05.ConclusionSleep disturbances may be an important factor to investigate in those with a history of participation in American football.
What words and concepts do people enrolled in research registries use to describe them?
Authors: Harkins Kristin , Maloney Erin , Bleakley Amy , Langbaum Jessica B 
Published: December 2021

AbstractBackgroundResearch registries have been developed as a strategy to accelerate enrollment into Alzheimer’s disease studies. However, there remains a need to increase both total enrollment and diversity of race and gender among registry enrollees and study participants. The goal of this study was to learn how enrollees describe registries with a focus on identifying preferred terminology in order to improve outreach and recruitment efforts.MethodIndividuals enrolled in two registries (Penn Memory Center Brain Health Research Registry and Banner Alzheimer’s Institute Alzheimer’s Prevention Registry) were invited to complete an anonymous online survey. Items included demographic characteristics and open‐ended questions about how they would describe a brain health research registry. Data were collected December 2020 through January 2021 from 1,741 respondents who completed the survey. Respondents were primarily non‐Hispanic White (75.8%) and female (58.4%). To ensure diverse representation in the analysis and allow comparisons by race and gender, equally sized (n=49) random samples of respondents (Hispanic/Latinx; non‐White; non‐Hispanic White females; non‐Hispanic White males) were selected for coding and analysis in NVivo. The University of Pennsylvania IRB approved this study.ResultsRespondents use a wide range of terminology to describe registries (“pool,” “bank of names,” “roster,” “clearinghouse,” “gathering place,” “database,” “hub of communication,” “compendium,” “online community”) and the people enrolled in them (“volunteers,” “participants,” “members of the public,” “willing,” “interested”). Some describe participation as providing basic contact information, while others note features such as bloodwork, genetic tests, and periodic online tests and surveys. Respondents describe registries as allowing them to find, be notified of, or “matched” to studies. They frequently discuss registries as contributing to scientific knowledge and aiding development of preventions, treatments, and/or cures. Some also indicate that registries keep them informed about brain health. Voluntariness and data protection/privacy are mentioned less frequently. A small portion gave vague responses, indicated that they did not know what a registry is, or did not answer.ConclusionTerms and concepts that respondents use to describe registries vary and differ from those typically used by researchers. Applying respondent‐driven language and notions to outreach and recruitment efforts may facilitate more diverse and representative registry enrollment.
Gut microbiome‐related metabolites in plasma are associated with general cognition
Authors: Ahmad Shahzad , Arnold Matthias , Hankemeier Thomas , Ghanbari Mohsen , Uitterlinden André G. , Kraaij Robert , Van Duijn Cornelia M. , Kaddurah‐Daouk Rima F. , Kastenmüller Gabi , Ikram M. Arfan 
Published: December 2021

AbstractBackgroundIncreasing evidence suggests a role for gut microbiome in pathogenesis of neurological disorders including Alzheimer’s disease. Gut bacteria produce a large number of metabolites that become part of the human blood metabolome. We hypothesized that the effect of gut microbiome on Alzheimer’s disease is through certain metabolites derived or influenced by the gut microbiota. Identifying metabolites associated with gut microbiota as well as with general cognition may help to discover new targets for drugs and prevention.MethodWe profiled plasma samples of 1146 participants of the Rotterdam study for 1387 metabolites using a non‐targeted metabolomics platform. After preprocessing and quality control, plasma levels of 964 metabolites were available for analysis of 1040 participants. Gut microbiome information was available for participants based on 16sRNA sequencing (microbial taxa = 190). We evaluated the gut‐microbial association with metabolite levels in plasma using linear regression adjusting for age, sex, body mass index, medication use, and technical covariates. We further assessed these gut microbiota associated metabolites for association of metabolites with general cognition (G‐factor) using linear regression. Multiple testing correction was performed based on the false discovery rate (FDR) by Benjamini Hochberg (FDR<0.05).ResultWe found significant association of 400 metabolites (Grouped into xenobiotics, lipids, amino acids, peptides, co‐factor and vitamins, carbohydrates, energy and partially characterized molecules) with various gut microbial taxa. Among the gut‐microbiota‐associated metabolites, eleven also showed significant associations with general cognition after multiple testing. Among these associations, higher ergothioneine (xenobiotic) levels showed the most significant association with better cognition (β = 0.012, P = 6.40x10‐7). Ergothioneine showed significant association with genus RuminococcaceaeUCG003 (id 11361) (β = 0.064, P = 5.94x10‐5) and genus Romboutsia (id 11347) (β = 0.042, P = 1.98x10‐4), suggesting an implication of these genera in cognitive function mediated by ergothioneine.ConclusionOur study provides evidence for the association between gut microbiota and plasma metabolites of diverse biochemical groups, which also associates with cognition in a population‐based cohort. Further, studies are warranted to elucidate the complex relationship of gut microbiota, diet, genome, human metabolome, and cognition.
Baseline structural MRI and plasma biomarkers predict longitudinal structural atrophy and cognitive decline in early AD
Authors: Xie Long , Das Sandhitsu R. , Wisse Laura , Ittyerah Ranjit , de Flores Robin , Yushkevich Paul A. , Wolk David A. 
Published: December 2021

AbstractBackgroundIn clinical trials targeting early Alzheimer’s disease (AD), recruiting participants that are more likely to progress over the course of the trials is crucial to success. Molecular and neurodegenerative markers obtained through PET or in cerebrospinal fluid have significant prognostic value, but they are costly or invasive. In this study, we hypothesize that a combination of plasma and structural MRI biomarkers, which overcome these limitations, are predictive of longitudinal progression measured by atrophy and cognitive decline in early AD, providing a more feasible solution.MethodsLongitudinal 3 Tesla T1‐weighted MRI and cognitive measurements [logical memory, delayed recall and clinical dementia rating sum‐of‐boxes] of 662 cognitively normal (CN) and MCI participants [divided into β‐amyloid positive/negative (A+/A‐)] from ADNI were included (Table 1). Anterior/posterior hippocampus, entorhinal cortex, Brodmann areas (BA) 35 and 36, and parahippocampal cortex were segmented in baseline MRI. Annualized change rates of BA35 thickness [the first region of neurofibrillary tangle pathology] and cognitive measurements were estimated using linear modeling. In each diagnostic group and A+/A‐ subgroups, stepwise linear regression model with age, gender, education and intracranial volume as fixed variables and all baseline MRI and plasma measurements [neurofilament light chain (NfL), pTau‐181] was implemented to investigate their predictive power for each longitudinal measure. In addition, the area under the curve (AUC) of each model in discriminating the first and last terciles of each longitudinal measurement was reported.ResultsBaseline plasma and structural biomarkers provided complementary information in predicting longitudinal atrophy and cognitive decline in controls and MCI (Table 2, Figure 1). These relationships were maintained (albeit with some differences in most predicted measures) when limited to A+ subgroups (preclinical and prodromal AD, Table 4) with AUCs ranging from 0.70‐0.84. Interestingly, baseline structural measures are consistently included in all the models.ConclusionsWe demonstrated that baseline plasma and MRI biomarkers provide complementary information in predicting brain atrophy and cognitive decline. This indicates the combination of these biomarkers, which are relatively easy to obtain, may have important use for recruitment in clinical trials and practice. Additionally, the effect in A‐ CN indicates the potential use of our structural biomarker in predicting normal age‐related decline.
Spermidine supplementation and diffusion weighted imaging in subjective cognitive decline
Authors: Wurdack Katharina , Schwarz Claudia , Benson Gloria , Horn Nora , Antonenko Daria , Hofer Sebastian , Wirth Miranka , Sigrist Stephan , Madeo Frank , Flöel Agnes 
Published: December 2021

AbstractBackgroundSubjective Cognitive Decline (SCD) may represent an early, pre‐clinical manifestation of Alzheimer’s disease (Jessen et al., 2014), possibly accompanied by detrimental changes in white matter (WM) microstructure (Brueggen et al., 2019). Neuroprotective effects of increased external supply of spermidine were demonstrated in aged animal models (Madeo et al., 2018). This study investigated the effects of a 12‐month spermidine‐rich dietary supplementation on diffusion weighted imaging (DWI) parameters of central WM tracts in older persons with SCD.MethodThe monocentre, randomised, double‐blind, placebo‐controlled phase IIb SmartAge trial (clinicaltrial.gov: NCT03094546, Wirth et al., 2019) investigates the effects of a 12‐month dietary spermidine supplementation in SCD. Baseline and follow‐up DWI data were available for 72 SCDs (mean age 69±5 years; 38 placebo, 34 spermidine). Fractional anisotropy (FA) and mean diffusivity (MD) of central WM tracts were obtained through Tract Based Spatial Statistics. The interaction effect of intervention group and time was examined through analysis of variance. Exploratory analyses of within‐group changes from baseline to follow‐up were conducted using paired t‐tests. Correction for voxelwise multiple testing was applied.ResultNo statistically significant interaction effect of time and intervention group (spermidine vs. placebo) was present for FA and MD in central WM tracts. Exploratory within‐group analyses in the placebo group revealed a decrease of FA in areas comprising tracts within the limbic system and the MTL (right more than left), and an increase of FA in a small region of the right occipital lobe. Widespread increases of MD in the placebo group were observed in the right hemisphere and to a lesser extent in central regions of the left hemisphere. Within the spermidine group, no significant changes in FA or MD were present.ConclusionWhile our analyses did not show an interaction effect, we found detrimental within‐group changes in FA and MD from baseline to follow‐up in the placebo group but not in the spermidine group. Our findings thus suggest a potential beneficial influence of dietary spermidine supplementation on WM microstructure in SCD, to be followed up in future larger and longer‐lasting intervention studies.
NRG1/ErbB4 signaling and its role on the development and progression of Alzheimer's disease
Authors: García‐Colomo Alejandra , Nebreda Alberto , de Frutos Jaisalmer , Losada María Luisa Delgado , Higes Ramón López , Cuesta Pablo , Vilca Brenda Chino , Dolado Alberto Marcos , Maestú Fernando 
Published: December 2021

AbstractBackgroundAlzheimer’s disease (AD) is a complex disease; various etiopathogenic mechanisms, like genetics and cognitive reserve, affect its development and progression across the continuum. Neuregulin‐1 (NRG‐1) /ErbB4 signaling has been recently studied regarding its possible role in the development of AD. To our knowledge, the schizophrenia (SZ) risk SNPs rs6994992 (NRG‐1) and rs839523 (ErbB4) have never been explored in association to AD, but the risk alleles have been associated with structural, functional and cognitive alterations in SZ and healthy individuals. Some of these alterations are similar to those experienced by AD patients, over 40% of which evolve to experience psychotic symptoms. This subset of patients experience a more rapid cognitive decline, greater functional impairment, etc., which contribute to a greater level of distress for family and caregivers.MethodThe sample consisted of 584 Spanish individuals: 161 were diagnosed with mild cognitive impairment (MCI; age = 76.66±5.37). The remaining 423 were healthy controls (HC; age = 65.88±8.80).Participants underwent a neuropsychological evaluation, a MEG scan, a magnetic resonance imaging scan, and were genotyped for the rs6994992 and rs839523 SNPs.ResultPreliminary results show a significant interaction between the NRG1 risk allele and the diagnosis in the MMSE score (figure 1); the risk allele had no effect in HC, but in MCI those with the risk allele had a significantly worse performance. Linear models were performed for the prediction of the MMSE score, including either the NRG1 or ErbB4 SNP, the diagnosis, cognitive reserve and age. Significant interactions with the SNPs were found for both, including a three‐way interaction between the diagnosis, cognitive reserve.ConclusionThese preliminary findings could indicate that the SZ risk alleles have a negative influence in the AD continuum over cognition and, potentially, over structural and functional parameters. This effect could be modulated by cognitive activity across the lifespan.
Associations between CSF proteins and medial temporal lobe atrophy across the AD continuum
Authors: Ekblad Laura L. , Visser Pieter Jelle , Tijms Betty M. 
Published: December 2021

AbstractBackgroundCortical atrophy is a typical feature of Alzheimer´s disease (AD). The biological processes that associate with or possibly lead to atrophy remain largely unexplored. We hypothesized that disease stage would modulate the associations between cerebrospinal fluid (CSF) proteins and regional cortical thickness in individuals with abnormal CSF beta‐amyloid.MethodCognitively normal (CN), mild cognitive impairment (MCI) and AD individuals were selected from ADNI, based on abnormal CSF beta‐amyloid (<192 ng/l). All examined individuals had cortical thickness measurements and CSF proteomic data available (measured with MRM and RBM). Correlations between 217 CSF proteins and cortical thickness in 34 cortical regions (averaged over the left and right hemispheres) were analyzed with linear models, adjusted for age and sex. Interactions for diagnosis were evaluated for each protein‐cortical thickness association. Protein enrichment analysis was performed with Cytoscape ClueGO.ResultWe included 197 individuals (32 CN; 104 MCI; 61 AD) with a mean age 74.8 (SD 7.1) years, 41.6 % women.Cortical thickness declined according to disease progression in 28 brain regions, most significantly in the entorhinal cortex (ANOVA p‐value <0.0001), the middle temporal gyrus (p<0.0001) and the inferior temporal cortex (p<0.0001). 9 proteins, including phospho‐tau and BACE activity, showed interactions for diagnosis in the entorhinal cortex, 12 in the middle temporal gyrus and 19 inferior temporal cortex. These proteins were associated with beta‐amyloid metabolic process, dendritic cell differentiation, and oligodendrocyte development in ClueGO enrichment analyses. A consistent finding was that higher levels of the majority of these CSF proteins correlated with lower cortical thickness in CN, and that these correlations were attenuated with disease progression.ConclusionAlterations in the levels of CSF proteins are associated with cortical atrophy in the medial temporal regions, and the biological processes underlying cortical atrophy seem to begin already in the preclinical stage of AD. These results suggest that therapies targeted at preventing cortical atrophy would need to be initiated already in the CN stage.
Examining possible gender differences in the association between education and late‐life cognitive function in the LifeAfter90 Study, a large multiethnic cohort of the oldest‐old
Authors: Gilsanz Paola , Corrada Maria M , Mungas Dan M , Glymour M Maria , Kawas Claudia H , Lam Jennifer O , Vieira Katharine E , Peterson Rachel L , Eng Chloe W , Quesenberry Charles P , Whitmer Rachel A 
Published: December 2021

AbstractBackgroundEducational attainment predicts late‐life cognitive ability and dementia. Historically, women have had fewer educational opportunities than men. We examine if the association between educational attainment and cognitive level and decline differ by gender.MethodLifeAfter90 is an ongoing cohort of long‐time members of an integrated healthcare delivery system ≥90 years old without a dementia diagnosis at recruitment. Interviews and cognitive assessment occurred every six months and included self‐reported education (≤high school, some college, and ≥college graduate (reference)) and Spanish and English Neuropsychological Assessment Scales (SENAS). SENAS encompasses the domains of verbal episodic memory, semantic memory, and executive function. Mixed models with random intercepts estimated possible differences in the association between education and late‐life cognition adjusting for time (years since baseline), baseline age, race/ethnicity, and practice effects. Practice effects were accounted for by using an indicator variable for the first visit. Interactions terms allowed for possible gender differences in the association of education with baseline cognitive scores (i.e. education*male) and cognitive change (i.e., education*male*time).ResultThe 669 participants were on average 92.8 years of age, 63% were women, 34% were college graduates, and 69% were racial/ethnic minorities (Table 1 and Table 2). Lower levels of education were associated with worse performance on baseline cognitive assessment but not performance over time. Women with ≤high school or some college averaged worse baseline cognition in each domain than women who had completed college (Table 3). There was no significant gender by education interaction for verbal episodic memory (p‐value=0.22) or semantic memory (p‐value=0.26), but the disadvantage in executive function associated with lower education was significantly attenuated in men (some college*male β=0.32, 95% CI=0.08, 0.56; p‐value=0.01). There were no differences across genders in the association between education and any of the domain specific cognitive scores over time.ConclusionThe association between education and late‐life cognitive function appears to be similar across genders with the exception of college completion having a larger effect on baseline executive function scores for women than for men. We will continue to explore these differences as additional visits occur in this ongoing cohort of ethnically diverse oldest‐old individuals.