bluuebunny/crossref_metadata_2025_split huggingface dataset:
Individualized diagnostic and prognostic blood‐based models for use in clinical practice and trials
Authors: Hansson Oskar 
Published: December 2021

AbstractBackgroundBlood‐based biomarker’s for Alzheimer’s disease are likely to revolutionize the diagnostic work‐up in both specialized clinics and in primary care. Further, they might be used to identify suitable participants for preclinical and prodromal AD trials, i.e., individuals with AD pathology who will exhibit cognitive decline in the coming 2‐4 years.MethodWe evaluated the diagnostic and prognostic performance of plasma P‐tau181, P‐tau217, Ab42/40, and NfL in the prospective and longitudinal BioFINDER I and II studies. We compared the accuracy of plasma biomarkers with CSF AD biomarkers, amyloid‐PET and tau‐PET. Diagnostic and prognostic algorithms were typically validated in an independent cohort.ResultPlasma P‐tau alone could with very high accuracy differentiate AD dementia from other neurodegenerative diseases, and a plasma P‐tau217 assay was shown to be non‐inferior to tau‐PET and CSF biomarkers in this setting. A combination of plasma P‐tau and NfL could be used for individualized prediction of cognitive decline and conversion to AD dementia within 2‐ 6 years in patients with mild cognitive impairment (MCI), and this combination performed equal to CSF AD biomarkers. Further, in a population including both patients with subjective cognitive decline (SCD) and MCI, as often seen in primary care settings, an optimal prognostic algorithm for prediction of AD dementia included plasma P‐tau and brief cognitive tests of memory and executive function. We have developed an online tool for individualized prediction of AD dementia in cases with SCD or MCI (https://brainapps.shinyapps.io/PredictionADdementia/), which was shown to outperform the clinical prediction by memory clinic physicians. In cognitively unimpaired (CU) individuals we showed that plasma Ab42/Ab40 and P‐tau together could detect cerebral Ab pathology, but a combination of plasma Ab42/Ab40, P‐tau and NfL was needed for accurate prediction of subsequent cognitive decline and to enrich pre‐clinical trials with suitable research participants. Finally, results will be presented on the use of fully automated assays for quantification of relevant plasma AD biomarkers.ConclusionDifferent combinations of easily accessible tests are optimal during different disease stages of AD, and they are likely to be useful in both clinical practice and trials after validation in multiple large‐scale, relevant and diverse cohorts.
Exposure of non‐steroidal anti inflammatory drugs and risk of dementia based on National Sample Cohort data
Authors: Chae Wonjeong 
Published: December 2021

AbstractBackgroundOne of the most significant health problems caused by aging is dementia. The aim of this study was to investigate the impact of exposure to non‐steroidal anti‐inflammatory drugs to the risk for dementia.MethodData (2003–2013) from the Korean National Health Insurance Service‐National Sample Cohort was used. The study's 5‐year landmark period began on January 01, 2003. The Cox proportional‐hazard model was employed to analyze the effects of non‐steroidal anti‐inflammatory drug exposure on all‐cause dementia, Alzheimer’s disease dementia, vascular dementia, early‐onset dementia, and late‐onset dementia. Further analyses of non‐steroidal anti‐inflammatory drug types and their defined daily doses were also conducted.ResultOf the 555,643 individuals in the cohort, 21,809 (3.9%) had dementia. Compared to the never‐used non‐steroidal anti‐inflammatory drug group, the ever‐used non‐steroidal anti‐inflammatory drug group had a decreased risk for all‐cause dementia (HR: 0.91, 95% CI: 0.78–0.84) for those individuals who did not have all‐cause dementia during the landmark periods. The risk for subtype dementias was significantly lower in the case group. For types of non‐steroidal anti‐inflammatory drugs, ketorolac was found to have a decreased risk for all‐cause dementia (HR: 0.69, 95% CI: 0.53–0.91). For non‐steroidal anti‐inflammatory drug dosages, higher defined daily doses had a lower risk for all‐cause dementia.ConclusionThe data indicates that common non‐steroidal anti‐inflammatory medication use in the general population may contribute to a decreased risk for dementia, with the possibility of preventing dementia at a low cost so that the high cost and burden of treating dementia might be reduced.
Afternoon‐snack glycemic load is associated with plasma amyloid‐beta peptides in APOE4 carriers at risk of dementia
Authors: Gentreau Mélissa , Raymond Michel , Féart Catherine , Samieri Cécilia , Chuy Virginie , Berticat Claire , Artero Sylvaine 
Published: December 2021

AbstractBackgroundRecent evidence suggests that a high refined‐carbohydrate diet is a risk factor for dementia, especially among APOE4 carriers. Thus, refined‐carbohydrate diet may modify biomarkers of dementia, such as amyloid‐β (Aβ) peptides according to APOE4 carrier status. Here, we focus on afternoon‐snack glycemic load (GL) because snacks are generally richer in refined carbohydrates. We investigated the relationship between plasma Aβ, afternoon‐snack GL, and APOE4 carrier status in participants with or without incident dementia.MethodWe followed 377 non‐demented participants from the Three‐City Study (Bordeaux and Montpellier center), aged over 65, with plasma Aβ peptide concentrations measured at baseline. At 2‐year (Bordeaux center) and 4‐year (Montpellier center), the participants completed a semi‐quantitative Food Frequency Questionnaire which was used to estimate GL (GL assesses both the carbohydrate quantity and quality, and reflects glycemic response). At each follow‐up (every 2‐3 years during 15 years), participants had clinical diagnosis of dementia. We used linear regressions to evaluate the associations between plasma Aβ40, Aβ42, Aβ42/Aβ40 ratio and GL, APOE4 carrier status, and the interaction GL x APOE4, among participants with or without incident dementia. Models were adjusted for center, age, sex, education level, total cholesterol, serum creatinine and adherence to the Mediterranean diet.ResultThe sample included 60.2% of women and mean age of the participants was 76.1 (± 5.2) years. During the follow‐up, 51 participants developed dementia. Among dementia‐free participants, GL tended to be associated with Aβ42/Aβ40 ratio (β = ‐0.006 [SE = 0.003], P = .055) but not with Aβ40 and Aβ42 concentrations. Among incident dementia participants, the interaction GL x APOE4 was associated with plasma Aβ40 concentration (β = 54.2 [SE = 25.6] pg/mL, P = .042). Regarding Aβ42, no interaction was found. Regarding Aβ42/Aβ40 ratio, GL x APOE4 was no longer significant after adjustment (β = ‐0.038 [SE = 0.024] P = .124).ConclusionIn APOE4 carriers with incident dementia, a higher afternoon‐snack GL was associated with worse plasma Aβ peptide concentrations. These results highlight that rich refined‐carbohydrate diet is a modifiable risk factor for plasma Aβ peptide concentrations and subsequent dementia risk. Experimental studies are required to explain potential mechanism involved.
Population attributable fractions for modifiable risk factors of dementia in cognitively normal and MCI populations: Data from two countries
Authors: Wezeman Sandra , Uleman Jeroen F , Peeters Geeske , Margioti Eleni , Scarmeas Nikolaos , Olde‐Rikkert Marcel 
Published: December 2021

AbstractBackgroundPrevious studies have shown that population‐wide up to 40% of all dementia cases are related to twelve modifiable risk factors, which thus calls for preventive measures. To inform health promotion strategies, it is important to know whether the risk attributable to modifiable risk factors differs in cognitively healthy persons and persons with Mild Cognitive impairment (MCI). This study analyzed associations and population attributable fractions (PAFs) of twelve modifiable risk factors with dementia in cognitively healthy and declining (MCI) adults aged ≥65 years, in two cohort studies from the US and Greece.MethodData were from the National Alzheimer’s Coordinating Centre (NACC) (n=16,147, impaired‐not‐MCI n=1007, mean age 75.2 ±6.9, 54.8% female) and the Hellenic Longitudinal Investigation of Aging and Diet (HELIAD) (n=1141, mean age 72.9 ±5.0, 58.0% female). PAFs were calculated based on hazard ratios (HRs) for the risk of dementia and risk factor prevalence in the NACC (9 risk factors) and HELIAD (10 risk factors) data. Weighted PAFs were calculated to adjust for communality between risk factors. Analyses were performed for the total samples, as well as separately for cognitively healthy participants and those with MCI at baseline.Result2,630 participants enrolled by the NACC developed MCI (25.1%) and 3,333 developed dementia (20.7%) during a mean follow‐up of 4.9 (±3.5) years. 131 participants developed MCI (11.2%) and 68 developed dementia (5.9%) during HELIAD follow‐up of on average 3.1 (±0.86) years. A relatively low weighted overall PAF of 21.4% was found in the total sample of the NACC study. The PAF was 20.8% in the cognitively normal subgroup and ‐6.17% in the MCI subgroup A relatively high weighted overall PAF of 60.7% was found for the total sample in HELIAD. The PAF was 78.4% in the cognitively normal subgroup and 80.6% in the MCI subgroup.ConclusionIn general, translating valuable global meta‐analysis data on modifiable risk factors should be carefully carried out per population before starting preventive interventions. Within each cohort, the PAFs for cognitively healthy and cognitively declining participants were in the same range, suggesting that also in persons with MCI, elimination of risk factors continues to be important.
A possible novel mechanism for cognitive resistance to neurodegeneration: modulation of interneuron activity in the hippocampus after exposure to enriched environments
Authors: Khan Zuhayr M , Kageyama Glenn 
Published: December 2021

AbstractBackgroundExposure to an enriched environment has been shown in many studies to be beneficial to brain structure and cognition by preserving neuronal integrity and strengthening the functioning and plasticity of neural circuits. These benefits derive from the added spatial, social, and sensory complexities in an enriched environment. It has been well known for a few decades that an enriched environment stimulates neurogenesis and cell proliferation in the dentate gyrus of the hippocampus, leading to an increased number of dentate granule cells (DGCs). However, the changes to other populations of cell types, particularly interneurons, has remained elusive. Interneurons are integral regulators of neurotransmission in the hippocampus. Damage to hippocampal interneurons have serious implications and lead to a decline in cognitive health. Our study sought to elucidate possible changes in interneurons affected by exposure to an enriched environment (EE) and enriched changing (EC) environment.MethodThe topographic distribution of nicotinamide adenine dinucleotide phosphate‐diaphorase (NADPHd) positive neurons was studied in the dentate gyrus of the rat dorsal hippocampus.ResultEnvironmental enrichment increased the number of NADPHd positive neurons found in both enrichment groups. The elevated level of neurons was represented uniformly across almost all six layers of the dentate gyrus and was most significant in the expected granular cell layer (GRCL) and subgranular zone (SGZ).ConclusionThe overall preliminary results suggest that the brain has the ability to adapt to increased amounts of sensory stimulation. These changes highlight a possible new mechanism of physiological homeostasis and physical evidence of a cognitive reserve; with an increased demand for energy from new‐born DGCs and increased sensory input, the brain will regulate its energy expenditure via an increase in either the activity of existing interneurons, or the actual number of interneurons. Further research will involve running a restudy and observing the differences to the ventral hippocampus, CA1, and CA3 regions, and the effects on specific subpopulations of interneurons.
The gut microbiome and cognitive function in midlife: The CARDIA study
Authors: Meyer Katie A 
Published: December 2021

AbstractBackgroundBased on experimental and clinical studies of specific patients, a gut‐brain axis has been hypothesized as mechanism connecting peripheral metabolic and immunologic activity to the brain, including cognitive functioning. Few studies have investigated the association of gut microbial composition to cognition in large community samples.MethodCross‐sectional data were from a subsample (n=597) of participants in the U.S.‐based bi‐racial Coronary Artery Risk Development in Young Adults (CARDIA) study (2015‐16). Participants were aged 48‐60 years, 45% male, and 45% Black (Table). V3‐V4 regions of 16S rRNA were sequenced from stool DNA with Illumina MiSeq technology and. microbial taxonomic measures generated from the sequenced data. After filtering out rare taxa, 107 genera (of 375 originally assigned) were included in the analysis. Participants completed six interviewer‐administered cognitive tests: Montreal Cognitive Assessment (MoCA), Digit Symbol Substitution Test (DSST), Rey‐Auditory Verbal Learning Test (RAVLT), timed Stroop test, and letter and category fluency tests. Higher scores on all tests reflect greater cognitive functioning, except for Stroop, for which faster (lower time) is better.ResultRegression analysis of cognitive test scores on genera included adjustment for sequencing batch; and participant age, sex, race, BMI, and diabetes. Eleven genera were associated with two or more cognitive measures at FDR<0.10, and 31 genera were associated with two or more at FDR<0.20 (Figure): Barnesiella was positively associated with DSST and category fluency; Lachnospira was positively associated with DSST, RAVLT, MoCA, category fluency, and negatively associated with the timed Stroop test; Sutterella was negatively associated with MoCA, RAVLT, and DSST. Seven of the 11 genera with shared associations at FDR<0.10 (and 22 of the 31 at FDR<0.20) were from within the Clostridia class.ConclusionTests of global cognition and psychomotor speed were associated with specific microbes in the gut. These microbes, particularly those stemming from Clostridia class, may be involved in short‐chain fatty acid production and inflammatory pathways. Our data contribute to a growing body of literature suggesting that the gut microbiota may relate to cognitive function. These signals must be replicated and further researched to identify relevant genetic, metabolic, and inflammatory pathways.
Social engagement and cognitive decline in older African‐Americans: The Minority Aging Research Study
Authors: James Bryan D , Lamar Melissa , Lange‐Maia Brittney S , Capuano Ana W , Barnes Lisa L 
Published: December 2021

AbstractBackgroundSocial engagement in later life is associated with lower rates of cognitive decline and dementia, but most research has been conducted in primarily White cohorts. Little is known about this relationship in older African Americans, and some promoters of cognitive reserve in Whites may not have the same benefits in African Americans.MethodsWe used data from the Minority Aging Research Study (MARS), a study of community‐dwelling African American older adults in Chicago. Social activity was measured using an 8‐item scale assessing frequency of participation in activities involving social interaction (mean=2.5, SD=0.5). Social network size was assessed as the number of children, family, and friends seen at least once a month (mean=6.4, SD=6.0). Loneliness was measured with a 5‐item Likert scale assessing perceived emotional isolation (mean=2.1, SD=0.6). Life space is a measure of spatial movement through 6 zones of the environment from bedroom (smallest) to out of town (largest) (mean=5.5, SD=0.9). Global cognitive function was the average of z‐scores for 19 standard cognitive tests. Linear mixed models were used to test for associations with level and rate of change in cognitive function, with terms for each social engagement variable at baseline, age at baseline, sex, education, time since baseline, and interactions with time.ResultsParticipants (n=768; mean age=73.5, SD=6.3) were followed for an average of 6.3 years (SD=4.6). Higher social activity was related to slower cognitive decline (est=0.021, SE=0.008, p=0.011), but not to level of cognitive function (est=0.052, SE=0.036, p=0.15). Alternately, loneliness and a larger life space were not related to cognitive decline (est=0.003, SE=0.007, p=0.64; and est=0.001, SE=0.005, p=0.82, respectively), but were related to level of cognitive function (est=‐0.104, SE=0.029, p<0.001; and est=0.062, SE=0.020, p=0.002, respectively). Social network size was not related to level or rate of change in cognition.ConclusionsIn older African Americans, social activity was related to less cognitive decline, while other measures of social engagement were related to level but not rate of change in cognitive function.
Generation of the AD Informer Set: Chemical tools to facilitate Alzheimer’s disease drug discovery
Authors: Potjewyd Frances M. , Annor‐Gyamfi Joel K. , Guduru Shiva K. R. , Nwogbo Felix , Rogers David A. , Hopkins Meghan D. , Conlon Ivie , Wells Carrow , Stashko Michael , Hardy Brian P. , Wang Xiaodong , Frankowski Kevin , Kireev Dmitri B. , Pearce Kenneth H. , Willson Tim , Aubé Jeff , Frye Stephen V. , Richardson Timothy , Young Jessica E. , Axtman Alison D. 
Published: December 2021

AbstractBackgroundCurrently, treatments for Alzheimer’s disease (AD) predominantly include acetylcholinesterase inhibitors, which address the symptomatic effects of the disease. The discovery of disease modifying interventions in the development and progression of AD are critical as there are currently no drugs or biologics which can elicit disease modifying effects. Promisingly there is an increase in the number of novel therapeutic strategies targeting AD that have progressed to clinical trials, and interrogation of targets implicated in AD pathology remains an area of extensive research.MethodTo assist the discovery of novel strategies that slow or halt AD pathology we have generated the AD Informer Set, the first iteration of which contains more than 150 chemical tools. We will make solutions of the physical set as well as all associated data available to the scientific community in 2021. Further data is being collected on compound kinetic solubility, pharmacokinetic properties, potential off‐target liabilities, and AD‐specific readouts, including mitochondrial metabolism, oxidative stress and glycolysis, and effects on p‐Tau and Aβ expression levels.ResultThe AD Informer Set includes compounds for targets that have AD implicated biology, either well validated or recently suggested, and contains relevant information about the gene, compound structure and activity, and associated AD phenotypes. 1, 2
ConclusionThe AD Informer Set will be shared with the scientific community at large to qualify assays, interrogate target validity in AD models, and to provide positive controls to aid in the discovery of new chemical entities. References: (1) Hodes RJ, Buckholtz N. Accelerating Medicines Partnership: Alzheimer's Disease (AMP‐AD) Knowledge Portal Aids Alzheimer's Drug Discovery through Open Data Sharing. Expert Opin Ther Targets. 2016, 20, 389‐91. PMID: 26853544. (2) Mullard A. NIH launches open science Alzheimer initiative. Nat Rev Drug Discov. 2019, 18, 895. PMID: 31780852.
Clinical diagnosis of Alzheimer’s disease: Recommendations of the International Working Group (IWG)
Authors: Villain Nicolas , Dubois Bruno , Frisoni Giovanni B. , Rabinovici Gil D. , Sabbagh Marwan Noel , Cappa Stefano , Bejanin Alexandre , Bombois Stéphanie , Epelbaum Stéphane , Teichmann Marc , Habert Marie‐Odile , Nordberg Agneta K. , Blennow Kaj , Galasko Doug R. , Stern Yaakov , Rowe Christopher C. , Salloway Stephen P. , Schneider Lon S. , Cummings Jeffrey L. , Feldman Howard H. 
Published: December 2021

AbstractBackgroundIn 2018, the National Institute of Aging and the Alzheimer Association proposed a purely biological definition of Alzheimer’s disease (AD) relying on biomarkers. While the intended use of the framework was for research purposes, it has engendered debate and challenges regarding its application in everyday clinical practice. For instance, cognitively unimpaired individuals may have biomarker evidence of both amyloid and tau pathology, but may never develop clinical manifestations in their lifetime. Furthermore, a positive AD pattern may be observed in other brain diseases where AD pathology is present as co‐pathology. In this presentation, the international Working Group (IWG) presents what we consider to be the current limitations of biomarkers in the diagnosis of AD, and on the basis of this evidence we propose recommendations for how biomarkers should and should not be used for diagnosis of AD in a clinical setting. We recommend that AD diagnosis be restricted to the occurrence of positive biomarkers together with specific AD phenotypes, whereas biomarker positive cognitively unimpaired individuals should be considered only at‐risk for progression to AD.
Effects of a lifestyle intervention on daytime sleepiness and cognitive function
Authors: Hayden Kathleen M , Spira Adam P , St‐Onge Marie‐Pierre , Ding Jingzhong , Anderson Andrea , Molina‐Henry Doris P , Sanderlin Ashley H , Reboussin David M , Espeland Mark A , Bahnson Judy 
Published: December 2021

AbstractBackgroundDaytime sleepiness is common in older adults and may result from poor nighttime sleep due to sleep disordered breathing, fragmented sleep, or other sleep disorders. Daytime sleepiness may signify disruption of circadian rhythms and disorder in neural circuitry arising from neurodegenerative disease. We investigated the association between self‐reported daytime sleepiness and cognitive function in Look AHEAD, a randomized clinical trial of an intensive lifestyle intervention (ILI) in a cohort of adults with type 2 diabetes (T2D) and overweight or obesity at baseline.MethodParticipants (aged 45‐76 years) were randomized to ILI or diabetes support and education (DSE) conditions. After ∼10 years, the trial was stopped; observation continued to year 18. We included participants who reported levels of daytime sleepiness at baseline and year 18 (n=2,825). Change in daytime sleepiness was defined as increasing, stayed the same, or decreasing levels of daytime sleepiness. Cognitive assessments at years 13 and 18 included measures of global function, memory, executive function, and attention; a cognitive composite was derived from z‐score averages. The relationship between change in daytime sleepiness from baseline to year 18, and cognitive function at year 18 was examined using analysis of covariance, adjusting for year 13 cognitive performance, baseline age, gender, race/ethnicity, education, APOE ε4 carrier status, baseline CVD history, and baseline daytime sleepiness.ResultParticipants who reported increased daytime sleepiness from baseline to year 18 (n=402), performed significantly worse on the cognitive composite than those who reported no change (n=1089) or decreased levels of daytime sleepiness (n=948), (Least Squares Mean [standard error]) ‐0.50 (0.04); ‐0.40 (0.03), and ‐0.39 (0.03), respectively; p‐value=0.004. Significant interactions between treatment arm and daytime sleepiness were found in executive function (p<0.10) and memory (p<0.001) such that relationships were stronger among ILI compared with DSE participants including poorer scores among those with increasing daytime sleepiness in the executive function (34.3 (0.72); p<0.02); and memory domains (6.5 (0.30); p<0.05).ConclusionIncreasing daytime sleepiness over 18 years predicted poorer cognitive performance in older individuals at high risk for sleep disorders. ILI may exacerbate relationships between increasing daytime sleepiness and cognitive deficits in adults with T2D and overweight/obesity.