bluuebunny/crossref_metadata_2025_split huggingface dataset:
APOE‐e4, microbiota and inflammation in healthy elderly
Authors: Marizzoni Moira , Cattaneo Annamaria , Mirabelli Peppino , Mombelli Elisa , Andryszak Paulina , Nicolosi Valentina , Roux‐Lombard Pascale , Salvatore Marco , Frisoni Giovanni B. 
Published: December 2020

AbstractBackgroundApolipoprotein E (APOE) ε4 allele is the main genetic risk factor for AD and has different roles in modulating the disease process along with the continuum from intact cognition to dementia due to AD, with its strongest influence at the earliest stages. The aim of this study is to test our hypothesis that places APOEε4 as a trigger in the perturbation of gut microbiota homeostasis.MethodFecal samples were collected from 28 cognitively intact elderly with known APOE genotype. Bacterial 16S rRNA gene was sequenced according to the 16S‐protocol on MiSeq (Illumina). Taxonomic abundance was computed with the free software package QIIME 2 (Quantitative Insights into Microbial Ecology; Bokulich, Microbiome, 2018; https://qiime2.org/). Plasma levels of cytokines were measured using a commercially available multiplex beads immunoassay, based on the Luminex platform.ResultAPOEε4 carriers showed altered abundance in 5 genera (LEfSe, p<0.048), 3 more (Bifidobacterium, Actinomyces, Lactococcus) and 2 less (Ruminococcaceae UCG‐003, Candidatus Melainabacteria) abundant, as well as decreased blood levels of IL‐8 (p=0.047) compared with non‐carriers. Elevated abundance of Bifidobacterium, Actinomyces, Lactococcus were associated with decreased levels of IL‐8 and IL‐6 (rho<‐0.41, p<0.040).ConclusionStructural microbiota alterations are associated with the restraint of some peripheral pro‐inflammatory signaling pathways in healthy subjects at genetic risk for AD. As a “good” form of inflammation (i.e. I‐6, IL1‐beta, TNF‐alpha) has been proposed to be beneficial in the early phases of the disease in several AD mouse models (Chakrabarty, J Neurosci 2010; Shaftel, J Neurosci 2007), these preliminary data suggest that the deleterious impact of the APOE4 allele on AD development might start in the gut.
Heterogeneity in longitudinal deterioration of white matter microstructural integrity in the population and its implications for cognitive aging
Authors: Poulakis Konstantinos , Reid Robert I. , Przybelski Scott A. , Knopman David S. , Graff‐Radford Jonathan , Lowe Val J. , Mielke Michelle M. , Machulda Mary M. , Jack Clifford R. , Petersen Ronald C. , Westman Eric , Vemuri Prashanthi 
Published: December 2020

AbstractBackgroundWhite matter (WM) changes are widely seen in the elderly due to aging and pathological processes and have significant impact on cognitive aging. It is critical to understand the heterogeneity and drivers (causes) of the longitudinal deterioration of WM microstructural integrity, especially in a population‐based sample, to provide mechanistic insights into cognitive and brain aging.MethodLeveraging longitudinal diffusion tensor imaging (DTI) data from Mayo Clinic Study of Aging, we assessed whether individuals clustered based on distinct longitudinal fractional anisotropy (FA) trajectories. A total of 533 subjects (487 cognitively unimpaired, 62 with mild cognitive impairment and 4 with dementia diagnosis) aged ≥ 60 years and with at least two DTI scans (125 subjects had at least 3 scans) were included. To identify clusters of individuals with common FA profiles over time, we applied an in‐house longitudinal Bayesian mixed‐effects clustering analysis framework to the imaging data. Age at MRI accounted for the longitudinal component of the model, while sex and APOE4 carrier status were used as fixed effects.ResultWe identified four distinct clusters (Figure 1). We found that most WM tracts decline with age across all clusters but brainstem and association fibers were least likely to decline with aging. APOE4 carriership and amyloid deposition did not differ between the clusters. We found a resilient cluster of individuals (34%) (cluster 1) with better baseline WM and systemic vascular health who had a slower rate of cognitive and WM integrity decline over time. These individuals had highest baseline commissural and association fibers. The resilient group was in contrast to an “at risk” cluster of individuals (16%) (cluster 2) who had lower baseline WM integrity and systemic health and declined the fastest in both WM health and cognition over timeConclusionLongitudinal clustering of WM tracts provided insights into the differential aging of WM in the population which may be unrelated to Alzheimer’s disease pathophysiology. Measuring overall WM health and vulnerable tracts in the elderly can be useful as biomarkers and aid in the identification of “at risk” groups for prevention of future cognitive decline.
APOE‐ε4 and hippocampal volume in the cognitively healthy elderly: Longitudinal analysis reveals origins of apparent cross‐sectional differences
Authors: Zhang Linda , Duenas Eva , Long Christopher , Navas Susana , Calero Miguel , Medina Miguel , Strange Bryan A 
Published: December 2020

AbstractBackgroundThe Apolipoprotein Ε (APOE) ε4 allele is associated with increased susceptibility to Alzheimer’s disease (AD), but its effects on cognition and brain morphology in cognitively normal (CN) elderly are unclear. Using cross‐sectional and longitudinal data, this study aims to determine whether CN elderly adults with the APOE ε3/ε4 genotype show any differences in cognitive performance and neuroimaging measures.Method788 CN elderly men and women (aged 69‐86) were selected from the baseline visit of the Vallecas Project cohort based on genotype (APOE ε3/ε3 (n=648), ε3/ε4 (n=140)). Of these 788 subjects, 230 (aged 69‐75 at baseline; APOE ε3/ε3 (n=192), ε3/ε4 (n=38)) stayed in the project for at least 5 years, and were selected for longitudinal analysis. All participants underwent detailed neuropsychological and neurological evaluation, and MRI scanning at 3T. Neuropsychological test scores and neuroimaging measures (grey matter density, white matter diffusivity, global brain and hippocampal volumes (HV)) were analysed.ResultFrom the cross‐sectional analyses, there was a significant genotype‐by‐age interaction in right HV (F (1, 781)=6.06, p=0.014), with ε3/ε3 homozygotes displaying significantly larger volumes before age 75, but similar sized volumes to ε3/ε4 genotypes after age 75 (Fig. 1). However, for the longitudinal subgroup, neither baseline right HV nor its rate of atrophy over 5 years was significantly different between the two genotypes (Fig. 2). A significant genotype‐by‐number of visits interaction (F (1, 433)=6.18, p=0.013) in baseline right HV was found (Fig. 3). Comparison of neuropsychological test scores and other neuroimaging measures did not reveal any significant effects.ConclusionWe conclude that elderly subjects with APOE ε3/ε4 genotype who stay cognitively normal throughout a 5‐year study duration are not cognitively nor morphologically distinct from those with APOE ε3/ε3 genotype, most likely due to a survival effect.
Computerized decision support to select memory clinic patients for amyloid PET: Which patient to test?
Authors: Rhodius‐Meester Hanneke FM , van Maurik Ingrid S. , Koikkalainen Juha , Tolonen Antti , Frederiksen Kristian Steen , Hasselbalch Steen Gregers , Soininen Hilkka , Herukka Sanna‐Kaisa , Remes Anne , Barkhof Frederik , Van Berckel Bart N.M. , Scheltens Philip , Lötjönen Jyrki , van Der Flier Wiesje ,   the Alzheimer’s Disease Neuroimaging Initiative
Published: December 2020

AbstractBackgroundThe current diagnostic criteria allow the use of amyloid biomarkers (either CSF or PET) to provide pathophysiological support for the diagnosis of AD. How these criteria should be operationalized by clinicians is unclear. We previously developed a model to select patients in which CSF measurements have added value [1]. Now, we study whether the model can also be used to select patients for amyloid PET.MethodWe included 348 subjects (223 controls, 125 Alzheimer’s disease dementia) from ADNI2, with available neuropsychology, MRI and Florbetapir PET. Positive (AD like) and negative (normal) amyloid PET were simulated to estimate whether knowledge of amyloid status would impact (confidence in) diagnosis. These simulated markers were added to available demographic, neuropsychology and MRI data in each patient to see whether the diagnostic confidence increased. If the confidence exceeded a predefined cut‐off (probability of correct class (PCC)≥0.80), then the patient was selected for amyloid PET (computerized decision support approach). We compared this approach with proportion of PET scans and patients diagnosed with sufficient confidence (PCC ≥0.80) based on an algorithm without amyloid PET (only neuropsychology and MRI), and amyloid PET for all patients (see Figure 1).ResultThe computerized decision support approach recommended amyloid PET in 11%, which yielded a diagnosis with sufficient confidence in 75% of all patients. This approach was most efficient when compared to amyloid PET in none (0% amyloid, 71% diagnosed), or amyloid PET for all (100% amyloid, 71% diagnosed). Results were comparable for CSF instead of amyloid PET.ConclusionThe previous developed computerized decision support approach showed favorable results in selecting patients for amyloid PET testing. In this clear‐cut comparison between controls and AD, amyloid PET adds little over clinical measures – but a similar framework may help to support decision making in more realistic and challenging clinical situations. Expansion of this study is needed with a real life cohort consisting of patients with different types of dementia. In this way, the approach can support clinicians in making a balanced decision in ordering additional biomarker testing. Reference: (1) Rhodius‐Meester HFM et al. Selection of memory clinic patients for CSF, PLoS One. 2020;15(1).
Survival differences in ethnic minorities with dementia: A systematic review and meta‐analysis
Authors: Co Melissa , Couch Elyse , Gao Qian , Martinez Andrea , Das‐Munshi Jayati , Prina Matthew 
Published: December 2020

AbstractBackgroundIn the US and UK, some minority ethnic (ME) groups are thought to be at higher risk for developing dementia while simultaneously accessing care less frequently. Despite this, studies from both countries have suggested that ME groups may actually survive longer after a dementia diagnosis. We conducted a systematic review and meta‐analysis to investigate survival differences in dementia between ethnic groups in the literature.MethodWe searched Embase, Global Health, Ovid MEDLINE, and PsycINFO from inception to November 2018 for longitudinal observational studies which quantified racial/ethnic differences in mortality in dementia. Studies were included if they used ethnicity or race as a predictor for all‐cause mortality and reported a comparison between multiple ethnic groups, regardless of whether this was the primary aim. Records were screened for inclusion in double. Study quality was assessed using the Newcastle‐Ottawa Scale. Narrative synthesis was used to analyze and report findings of all eligible studies. A subset of studies from the US was included in a random‐effects meta‐analysis with robust variance estimation.ResultWe identified 21 eligible articles: 17 from the US, three from the UK, and one from the Netherlands. Across countries, all studies but one found lower or no difference in survival in ME groups as compared to the reference population. In the US, five out of 12 studies reported lower mortality in African American/Black ethnic groups and seven out of nine reported lower mortality in Hispanic/Latino groups as compared to non‐Hispanic White groups. From the meta‐analysis (six studies; n=101,502), the pooled hazard ratio (HR) for all ME subgroups compared to reference was 0.77 (99% c.i. 0.48‐1.24), although heterogeneity was high. Separate meta‐analyses of Black/African American and Hispanic/Latino groups found lower hazard of mortality in both (Black/African American: HR=0.86, 95% c.i. 0.82‐0.91, I2 = 17%; Hispanic/Latino: HR=0.65, 95% c.i. 0.50‐0.84, I2 = 86%). Overall, study quality was mixed, and studies rarely reported how ethnicity was ascertained or defined.ConclusionAvailable literature indicates that ME groups, particularly Hispanic American and African American groups, may have lower risk of mortality in dementia. Lack of consistency in reporting ethnicity is an issue in the literature.
Neurofilament light and cognitive performance: Associations with amyloid and vascular pathologies in individuals with mild cognitive impairment
Authors: Bos Isabelle , Vos Stephanie J.B. , ten Kate Mara , Scheltens Philip , Engelborghs Sebastiaan , Frisoni Giovanni B , Blin Olivier , Richardson Jill , Bordet Régis , Verhey Frans R.J. , Tsolaki Magda , Popp Julius , Lovestone Simon , Streffer Johannes , Andreasson Ulf , Blennow Kaj , Barkhof Frederik , Zetterberg Henrik , Visser Pieter Jelle 
Published: December 2020

AbstractBackgroundNeurodegenerative, amyloid and vascular pathologies have all been associated with cognitive performance, but their interrelationship remains uncertain. We investigated the associations between cerebrospinal fluid (CSF) neurofilament light (NfL), a biomarker for neurodegeneration, with four different cognitive measures in individuals with mild cognitive impairment (MCI) with and without biomarker evidence of amyloid and vascular pathologies.MethodWe included 314 individuals with MCI from the EMIF‐AD Multimodal Biomarker Discovery study based on availability of data on CSF markers, MRI markers and cognitive data. CSF amyloid‐β42/40 ratio was used to determine amyloid status (A‐/A+). Vascular status (V‐/V+) was based on the presence of at least one abnormal vascular MRI marker (Fazekas≧2, lacunes>0, microbleeds>0). Linear mixed models, with center as random factor, were used to test associations between NfL and four pooled cognitive outcome measures (memory z‐score, language z‐score, executive functioning z‐score and an attention z‐score) and the interaction with amyloid and vascular status.ResultOn average individuals were 69.2 (SD 7.6) years old and 51% were female. Seventyseven (25%) were classified as A‐V‐, 49 (16%) as A‐V+, 103 as A+V‐ (33%) and 85 (27%) as A+V+. The A+V+ group had significantly higher levels of NfL compared to the A‐V‐ group (p=0.026). There were no other differences between the groups on NfL levels. We found that NfL levels were associated with lower memory (β=‐0.019, p=0.037) and language (β=‐0.022, p=0.019) scores, but not with attention or executive functioning scores. In addition, the associations between NfL levels and memory scores were driven by the individuals with vascular pathology (A‐V+ p=0.007, A+V+ p=0.044) and the association with language scores was driven by the A‐V+ group (p=0.040). Figure 1 shows the relationship between cognitive outcome measures and NfL levels in the AV groups.ConclusionHigher NfL levels were associated with lower memory and language scores, in particular in patients with vascular pathology. NfL was not associated with attention and executive functioning scores and it was not associated with cognitive performance in patients with isolated amyloid pathology. These results could indicate that high NfL levels in prodromal Alzheimer’s disease may be proxy for underlying vascular pathology.
Is hippocampal volume an accurate and reliable early marker of Alzheimer’s disease?
Authors: Gentreau Mélissa , Maller Jerome J , Meslin Chantal , Cyprien Fabienne , Ritchie Karen , Artero Sylvaine 
Published: December 2020

AbstractBackgroundIt is challenging to predict when and which individuals will progress to Alzheimer's disease (AD) to facilitate enrollment in clinical trials. Hippocampal volume (HV) considered as a fundamental structure for cognition is one of the key emerging imaging markers to improve Alzheimer’s disease risk prediction. There are numerous examples of HV reduction among patients with AD and those at risk for AD. However most evidence is derived from research cohorts or clinical populations with short follow‐up, and the extent to which hippocampal degeneration predict long‐term AD remains somewhat unclear. Moreover, hippocampus being damaged by a variety of stimuli including nutrition, sleep, inactivity, stress and depressive symptoms, it may also play a role on mild cognitive decline in the context of normal aging. To address this issue we studied the long term association between HV and the risk of 1) incident dementia and 2) mild cognitive decline in normal aging.MethodWe studied 510 dementia‐free persons from the ESPRIT cohort, aged over 65 years. All participants underwent magnetic resonance imaging (1.5 T) at baseline. We used both manual and automated methods (Freesurfer 6.0) to measure HV. A cognitive test battery (global cognition, visual memory, executive function, verbal fluency) was performed, and participants were followed by neurologists for incident dementia at 2, 4, 7, 10, 12 and 15 years. We tested the association between HV and the risk of dementia and mild cognitive decline using respectively Cox proportional hazards and linear mixed models.Result42 participants developed AD. After adjustment by potential confounder (age, sex, education, ApoE4, depression, antidepressive drugs, alcohol, sleep, baseline MMSE score, intracranial volume) right and left HV were significantly associated with dementia (p<0.01) but also with mild cognitive decline in normal aging (p<0.02).ConclusionIn a community‐dwelling population, we report evidence that HV predict both long term incident dementia and mild cognitive decline in normal ageing casting doubt on the utility of this structure as an early biomarker of AD using only a single measure. However, this measure could be used in general population framework to target subject at risk of cognitive decline and to develop preventive strategies.
Establishment of a reversal learning assay in rats to investigate the effects of novel compounds on executive function
Authors: Dunphy‐Doherty Fionn , Rouine Jennifer , Kozareva Danka , Sokolowska Ewa , Prenderville Jack 
Published: December 2020

AbstractBackgroundCognitive ability declines with age, ranging from normal age‐related decline (Craik and Bialystok, 2006), to mild cognitive impairment (Gauthier et al., 2006), and to dementias like Alzheimer’s disease (Perry and Hodges, 1999). One domain which is particularly affected is executive function (Lien et al., 2008). Attentional set‐shifting and reversal learning tasks have been widely used to quantify executive dysfunction in older humans (Robbins et al., 1998) and rats (Schoenbaum et al., 2006). Here, we describe the establishment of an operant conditioning task to assess reversal learning in rats. We investigated a series of pharmacological interventions, including drugs affecting cholinergic and serotonergic transmission, previously shown to have pro‐cognitive effects in animal models and humans.MethodThe reversal learning task utilises a rule learning (non‐match response) protocol with a reversal (match response) component. After a week’s habituation to the operant chambers and the task, male Sprague Dawley rats (n = 10 per group) were trained to a criteria of above 90% correct on the non‐match response (approximately 10 days). Following reversal of the correct response to the match response, rats received daily drug administration prior to the task. The reversal learning phase of the task continued until rats again achieved criteria (90% correct response).ResultA number of compounds have been assessed in this reversal paradigm. Pro‐cognitive effects have been observed both using nicotine (acetylcholine receptor agonist; P<0.05 on sessions 5‐8 of reversal compared to control) and SB‐399885 (5‐HT6 antagonist; P<0.05 on session 7 of reversal compared to control). A breakdown of test sessions into smaller trial bins has yielded a better temporal resolution of the data to assess changes within as well as between testing sessions.ConclusionThese data demonstrate the successful establishment of an operant reversal learning task in rats. The task is sensitive to pharmacological intervention and therefore can be used to investigate the potential pro‐cognitive effects of drugs under development for treatment of cognitive dysfunction associated with psychiatric and neurodegenerative disease. Future studies in aged animals and disease models will explore the possibility of employing the task to assess disease specific deficits in executive functioning.
A cost‐consequence analysis of early detection of AD in the MOPEAD project — A project within the EU research agenda IMI‐2
Authors: Wimo Anders , Belger Mark , Bon Jaka , Vugt Marjolein , Jessen Frank , Kramberger Milica G , Jamilis Laura , Johansson Gunilla , Rodrigo Adrián , Rodriguez‐Gomez Octavio , Sannemann Lena , Stoekenbroek Malou , Stomrud Erik , Gurrutxaga Miren , Valero Sergi , Vermunt Lisa , Waterink Lisa , Winblad Bengt , Zwan Marissa D. , Boada Mercè ,   MOPEAD
Published: December 2020

AbstractBackground“Models of Patient Engagement for Alzheimer's Disease” (MOPEAD), is a project within the EU‐Innovative Medicines Initiative (IMI‐2) research agenda, aiming at improving early detection of Alzheimer´s disease (AD).MethodsFour screening strategies (“runs“) were tested in five countries (Germany, the Netherlands, Slovenia, Spain and Sweden): Run 1 used a web approach, Run 2 held open houses at memory clinics, Runs 3 and 4 took place at clinics (primary care and type2‐diabetes specialist settings respectively). Persons at risk of AD were offered referral to a memory clinic (WP3). The primary health economic outcome was the cost per true positive case (TP) of mild cognitive impairment (MCI) or AD from the screened population. Also costs per screened case, cost per case entering the memory clinic and the number needed to screen (NNS) to identify a TP case were analysed. A comprehensive sensitivity analysis was accomplished.ResultsOf 2847 screened persons, 1117 screened positive, 398 were evaluated at WP3 and of those, 236 were diagnosed with AD or MCI. The cost per TP of those screened was 1,190€ in Run 4, 1,530€ in Run 3, 2,722€ in Run 2 and 3,115€ in Run 1. The results in the sensitivity analysis that was regarded as best to reflect real world were 1,443€/TP in Run 4, 1,856€ in Run 3, 2,714€ in Run 2 and 3,098€ in Run 1. The NNS was 6 in Run 4, 8 in Runs 2 and 3 and 30 in Run 1. The cost per screened was 103€ in Run 1, 338€ in Run 2, 204€ in Run 3 and 212€ in Run 4. There were great country differences.ConclusionAlthough Runs 3 and 4 had lower costs per TP/screened population than Runs 1 and 2, the capacity of Runs 3 and 4 to identify cases with AD‐risk must be discussed. Thus, new diagnostic strategies (Runs 1 and 2) may be valuable after modifications. For example, one challenge in Run 1 was to get in touch with people who screened positive, and in Run 2, the cost‐effectiveness may improve by integrating Run 2‐screening and memory clinics (diagnose confirmation).