bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cognitive and neurodegenerative profile differences between “mismatch MCI” (A+T‐N+ MCI) And “prodromal AD” (A+T+N+ MCI) increase with time
Authors: McCollum Lauren , Das Sandhitsu R. , Wang Jieqiong , Xie Long , de Flores Robin , Wisse Laura , Xie Sharon X. , Yushkevich Paul , Wolk David A. 
Published: December 2020

AbstractBackgroundPer the Amyloid/Tau/Neurodegeneration (A/T/N) framework, beta‐amyloid accumulates during preclinical Alzheimer’s Disease (AD), followed by tau, then neurodegeneration. As AD symptoms are most linked to tau and neurodegeneration, both are expected by the MCI stage of disease. Thus, A+T‐N+ MCI (“mismatch MCI”) is thought to have both AD pathophysiology and non‐AD pathology, with the latter (given absence of tau) driving neurodegeneration and symptoms. We investigate the cognitive and neurodegenerative profile of mismatch MCI compared to “standard” A+T+N+ MCI (“prodromal AD”).MethodA+ (by CSF) and N+ (by hippocampal volume <90th‐percentile for A+ dementia) MCI patients from ADNI2/GO were grouped by tau status (based on CSF p‐tau): mismatch MCI (T‐; n=44; 34 followed longitudinally) and prodromal AD (T+; n=84; 61 followed longitudinally) (Table 1). Baseline AVLT immediate‐memory first trial, AVLT delayed recall, animal naming (category fluency), and Trails‐B‐minus‐Trails‐A (executive function; log‐transformed) z‐scores were compared. Longitudinal cognition was analyzed using mixed‐effects models. A Kaplan‐Meier analysis compared dementia‐free survival. Whole‐brain voxel‐wise analyses compared cortical thicknesses of each MCI group to A‐ controls. Medial temporal lobe (MTL) subregion volumes, determined using ASHS‐T1 (Xie, 2019) on T1‐weighted MRI, were compared at baseline and longitudinally.ResultMismatch MCI had less baseline delayed‐recall impairment (Figure 1), but was similar on other domains. Time*group interaction terms for longitudinal cognition were all significant (p<0.05), indicating slower decline in mismatch MCI (Figure 2). Mismatch MCI had longer dementia‐free survival (Figure 3, p<0.001).Whole‐brain voxel‐wise analyses revealed differential cortical thinning in MCI groups VS controls, with prodromal AD having more extensive atrophy, especially in the MTL (Figure 4). Mismatch MCI had lower mean anterior‐to‐posterior hippocampal volume ratio (p=0.016). While baseline entorhinal cortex, BA35, BA36, and parahippocampal cortex volumes were comparable (both groups had significant atrophy compared to controls), mismatch MCI had slower atrophy in these regions and the hippocampus (Table 2).ConclusionMismatch MCI’s lower anterior‐to‐posterior hippocampal volume suggests possible enrichment in individuals with TDP‐43, a common non‐AD pathology, given previous work suggesting TDP‐43 preferentially affects the anterior hippocampus. Overall, these results support the concept that mismatch MCI and prodromal AD have different underlying pathologic profiles in light of their divergent cognition and neurodegenerative topography.
Omega6/omega3 ethanolamin‐containing plasmalogen (PlsEtn) ratio as a biomarker of Alzheimer's disease progression
Authors: Lorenzi Marco , Fleuriot Lucile , Debayle Delphine , Barelli Helene 
Published: December 2020

AbstractBackgroundSingle‐cell transcriptomic analysis of AD has revealed that myelination‐related processes are perturbed in brain, suggesting a key role in AD pathophysiology. Oligodendrocytes support neurons and signal transmission in the central nervous system by wrapping axons with myelin, a lipid‐rich membrane structure that depend on fatty acid synthesis and metabolism. Beside galactolipids, the major lipids of myelin are cholesterol and ethanolamin‐containing plasmalogens (PlsEtn). Polyunsaturated fatty acids (PUFA) such as docosahexaenoic acid (DHA, 22:6, omega3), eicosapentaenoic acid (EPA, 20:5, omega3), arachidonic acid (20:4, omega6), and monounsaturated fatty acid oleic acid (18:1, omega9) are the major constituent FA at the sn‐2 position of Pls. Among them, DHA is the most efficient to confer very specific physicochemical properties and membrane fluidity (Pinot et al., 2014).MethodOur results in lipidomics reveal that brain PUFAs‐Pls levels decrease importantly in cortex T1 and particularly in the frontal white matter (FWM) of AD individuals.ResultWe hypothesized that blood and brain phospholipids deficits could be closely associated with disease progression in AD. This hypothesis is corroborated by our previous results showing statistical association between PUFA‐phospholipids (PC, PE, PS) blood concentrations and brain atrophy and cognition in the ADNI cohort (previous communication at AAIC 2018). In follow‐up analyses, we further demonstrated that blood PUFAs‐PlsEtn deficits specifically related to demyelination present the most significative statistical association between an increase of the ratio omega6/omega3 and the increase of AD severity (high disease stage).ConclusionBlood omega6/omega3 PUFAs‐PlsEtn ratio could be a biomarker of the demyelination process observed in AD progression.
Tau formation is associated with microglial activation in more widespread cortical areas than is amyloid deposition
Authors: Leng Fangda , Hinz Rainer , Dani Melanie , Hampshire Adam , Gentleman Steve , Brooks David J , Edison Paul 
Published: December 2020

AbstractBackgroundMicroglial activation has been found surrounding amyloid plaques and neurofibrillary tangles in brains of Alzheimer’s subjects . In‐vivo imaging using 11C‐PBR28 (a marker of translocator protein over expressed in activated microglia) has demonstrated significant correlation between both amyloid (18F‐Flutematemol PET) and tau deposition (18F‐AV1451 PET). However, it is not clear whether tau or amyloid predominantly influence microglial activation.Methods11C‐PBR28, 18F‐Flutematemol, 18F‐AV1451 PET scans were performed on clinically diagnosed mild cognitive impairment and Alzheimer’s dementia patients (n=20). 90‐120 minute summed 18F‐Flutematemol, 80‐100 minute summed 18F‐AV1451 and 60‐90 minute summed 11C‐PBR28 images were created. Tracer uptake in cerebellar grey matter was then sampled and individual image was divided by cerebellar uptake. The images were then smoothed with 6mm FWHM and analysed. Multiple regression analysis was performed using by VoxelStats package with 11C‐PBR28 as dependent variable, and 18F‐Flutematemol, 18F‐AV1451 and age as independent variable. Correction for multiple comparison was applied based on random field theory.ResultsIn the current model, amyloid deposition was found to contribute to elevated microglial activation in the posterior part of the brain including bilateral temporal, occipital lobe and posterior cingulate. While tau deposition contributed to neuroinflammation in wide‐spread areas covering bilateral frontal, temporal, parietal, occipital lobe and cingulate cortex.ConclusionIn the current model tau deposition had more unique contribution to microglial activation in MCI and AD cohort, suggesting that tau formation has a stronger association with microglial activation which is independent of amyloid deposition.
A review of factors that contribute to sub‐optimal medication management for older adult with dementia in residential care settings: Nurses’ perspectives
Authors: Agboji Aderonke Oluwatoyin 
Published: December 2020

AbstractBackgroundMedication use can play an important role in the health and well‐being of people with dementia in the long‐term care facilities. However, nurses often find the process of managing medicines for this population to be complex and challenging. As a result, various strategies are being employed to facilitate the medication management process including altering or modifying medications, hiding medication in food or drink of residents, and deviation from the ‘rights’ of medication administration (Barnes et al., 2006; Mc Gillicuddy et al., 2017; Mercovich et al., 2014; Qian et al. 2018; Serrano Santos et al., 2016; Thomson et al., 2009; Verrue et al., 2011; Wright, 2002). These practices are associated with increased risk of medication errors (Kartunen et al., 2019). Despite this, factors contributing to these practices are not well understood.MethodA comprehensive search of CINAHL, Medline, SOCIndex, PubMed, and PsychINFO databases was conducted between November and December 2019. ProQuest Dissertations and Theses and Google Scholar were used to search for gray literature. No date limitation was applied. A modified form of standardized critical appraisal tool known as mixed method appraisal tool (MMAT) was used to assess the quality of the papers (Hong, Gonzalez‐Reyes, & Pluye, 2018). Nvivo was used to extract findings. Data synthesis was done using convergent synthesis approach, more specifically, thematic analysis (Hong et al. 2017).ResultThe search resulted in 806 unique titles for screening. A total of 96 abstracts were screened, after which a full‐text review conducted for 59 articles. After the full‐text review, 12 articles were eligible to be included in the final report. The findings highlighted 2 major factors: individual and system factorsConclusionThere is need for both individual and system interventions to facilitate safe medication management for residents with dementia.
A preliminary account of ARIA‐E in the ongoing open‐label extension phase of BAN2401‐G000‐201 in subjects with early Alzheimer’s disease
Authors: Swanson Chad J. , Lai Robert Y.K. , Bogoslovsky Tanya , Bradley Heather , Rabe Martin , Zhang Yong , Kramer Lynn D. 
Published: December 2020

AbstractBackgroundAmyloid related imaging abnormalities – edema/effusion (ARIA‐E) are a common finding with some anti‐amyloid antibodies. BAN2401 had an ARIA‐E incidence of 9.9% at the top dose of 10 mg/kg biweekly in the 18‐month Phase 2b study BAN2401‐G000‐201. All subjects with ARIA‐E were immediately discontinued per protocol, regardless of radiologic severity or whether symptoms were noted. Here, we assess preliminary ARIA‐E rates for 10 mg/kg biweekly BAN2401 in the ongoing open label extension (OLE), while exploring the ability to dose through ARIA‐E depending on severity and whether symptoms were observed.MethodsMagnetic resonance imaging (MRI) is conducted to monitor for ARIA‐E at 9wk, 3mo, 6mo, and 12mo over the first 12 months of BAN201 treatment in the OLE. Subjects who experience mild or moderate (severity) radiologic ARIA‐E and are asymptomatic continue dosing per protocol. Dosing is temporarily interrupted in cases of severe (moderate or severe in Japan) and/or symptomatic ARIA‐E and can be resumed up to 2 times upon resolution. Data are based on ongoing reports as of 16 January 2020.ResultsA total of 177 subjects from the core study received at least one dose of BAN2401 in the OLE, with 12 cases of ARIA‐E (2 subjects had ARIA‐E in the core) noted across the various core treatment groups during the extension. A total of 167 subjects underwent 9wk MRI, 159 subjects underwent 3mo MRI, 95 subjects underwent 6mo MRI, and 49 subjects reached 9mo of treatment. Among subjects treated with placebo in the core phase, 4/44 subjects had ARIA‐E to date in the OLE. Most events were identified at 9wk or 3mo MRI, and 11/12 cases are in ApoE4 positives. Subjects have continued with dosing in the presence of ARIA‐E in 6/12 cases (1 questionable, 1 mild, 4 moderate), and 5/6 dose‐interrupted cases have resumed dosing to date. Three (3) of the 12 cases were symptomatic, including symptoms of confusion, headache, visual disturbance. ARIA‐E and symptoms resolved in 2 cases, while one case is ongoing.ConclusionUpdated OLE data will be presented and compared to reported rates observed and modelled (Hussein et al, 2019) from the core study.
Reduced neuronal activity in Alzheimer’s disease and mild cognitive impairment measured by resting state fMRI
Authors: Haddad Seyyed Mohammad Hassan , Scott Christopher J.M. , Arnott Stephen R. , Ozzoude Miracle , Strother Stephen C. , Black Sandra E. , Borrie Michael , Finger Elizabeth , Tartaglia Maria Carmela , Kwan Donna , Beaton Derek , Symons Sean , Soddu Andrea , Menon Ravi S. , Montero‐Odasso Manuel , Bartha Robert 
Published: December 2020

AbstractBackgroundEarly pathological changes in mild cognitive impairment (MCI) and Alzheimer’s disease (AD) gradually decrease neuronal metabolism and function measured by PET and functional MRI (fMRI). These changes are often associated with cognitive decline and can help in the diagnosis of AD. However more sensitive indicators of the earliest stages of disease must be developed to detect disease prior to cognitive impairment. Recently, a novel neuronal activity (NA) metric was introduced based on resting‐state fMRI (rs‐fMRI) signal oscillations, which showed dramatically lower NA in AD. Here we introduced a more sophisticated and potentially more sensitive NA metric to identify subtle NA differences between three groups: normal elderly controls (NEC), MCI, and AD.MethodThe rs‐fMRI scans (TR=∼2400, ∼10 minute acquisition) were acquired at 3T from 8 MRI scanners in the Ontario Neurodegenerative Disease Research Initiative (AD group, N=40, aged 71.8 ± 8.1, 42% female; and MCI groups, N=80, aged 70.3 ± 8.3, 46% female), and the Gait and Brain Study (NEC group, N=30, aged 71.3 ± 6.0, 23.33% female). The rs‐fMRI signal was pre‐processed using FMRIB Software Library (FSL) and decomposed into independent components (ICs) using IC analysis. The ICs were classified into neuronal and non‐neuronal using a support vector machine classifier. The proposed voxel‐wise NA metric was defined based on similarity (cross covariance) between rs‐fMRI signal and neuronal ICs. This metric was utilized to create resting‐state NA map in each subject, which were compared between groups.ResultSingle subject and group average NA maps are provided in Fig. 1. The % difference maps between each group are shown in Fig. 2. The average voxelwise % difference in NA between groups was 38% between NEC and MCI, 38% between NEC and AD, and 10% between MCI and AD. Average NA in whole gray matter, hippocampus, posterior cingulate cortex, and precuneus, in each group are also provided in Fig. 3.ConclusionLower NA was clearly detected in AD and MCI groups compared to NEC. The large decrease in NA detected in MCI subjects compared to NEC suggests this metric is highly sensitive to early changes in neuronal function.
Education and its effect on risk and age at onset in Alzheimer disease (AD) in African Americans
Authors: Adams Larry D. , Slifer Susan H. , Ramos Jairo , Inciute Jovita D. , Starks Takiyah D. , Scott Aja M. , Lacroix Faina C. , Laux Renee A. , Haines Jonathan L. , Vance Jeffery M. , Cuccaro Michael L. , Byrd Goldie S. , Beecham Gary W. , Pericak‐Vance Margaret A. 
Published: December 2020

AbstractBackgroundIncreased years of education have been previously associated with a decreased risk of developing Alzheimer disease (AD) with cognitive reserve suggested as the source of the protective effect in Non‐Hispanic Whites (NHW). African Americans (AA) are twice as likely to develop AD compared to NHW. We investigated the hypothesis that education was similarly correlated with risk of AD in the AA population. We also examined the relationship of education and age at onset (AAO) of AD in AA.MethodParticipants consisted of 132 AA AD cases and 428 AA cognitively intact (CI) individuals 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 logistic regression to determine the effect of age, sex, education level and APOE4 status between cases versus controls. Additionally, using a linear model we examined the effect of education on AAO including sex and APOE4 status as covariates.ResultResults showed that increasing years of education had a protective effect on AD risk. Initially including sex and age as covariates, both higher education categories were significant, with 9‐12 years (p = 0.02;OR = 0.461[0.23,0.9])) and >12 years (p = 1.30e0‐04;OR = 0.26[0.13,0.41]). Adding APOE4 dosage (0(Ref), 1,2 alleles) to the model (significant at p = 9.54e‐05; p = 5.27e‐07), the effect of education remained significant (p = 0.03;OR = 0.46[0.23,0.93]) and p = 4.84e‐05;OR = 0.22[0.10,0.46]) for 9‐12 and >12, respectively further supporting its role in AD risk. We examined the effect of education on AAO. Education (8‐12 years) trended in significance (p‐value = 0.07; β = ‐3.76[‐7.82,0.307]) with >12 years significant (p‐value = 1.63e‐04; β = ‐13.07,‐4.25]) supporting later AAO with higher education. The effect of APOE4 on AAO was not significant (p = 0.226). APOE4 added to the model as a covariate did not have a significant effect on AAO, however, education levels continued trending (8‐12; p = 0.07; β = ‐3.76[‐7.86,0.34]) and significant (>12; p = 3.71e‐04; β = ‐8.33[‐12.84,‐3.82]).ConclusionThese data support the hypothesis that higher education results in a decreased risk of AD in AA regardless of APOE4 status. We also found a similar protective effect for a later AAO. Thus, the potential outcome of education on cognitive reserve appears across multiple racial backgrounds.
Development of a platform for the discovery of new Alzheimer’s disease drugs targeting stress‐induced neuroinflammation
Authors: Sebastian Maria , Pasinetti Giulio Maria Maria 
Published: December 2020

AbstractBackgroundSterile inflammation plays a detrimental role in neurodegenerative disorders, having an extraordinary impact on Alzheimer’s disease (AD). Stress signals, such as the alarmin high mobility‐group box‐1 (HMGB‐1), trigger activation of inflammasome complexes —as NLRP3 or NLRC4— and the subsequent oligomerization of the associated speck‐like protein containing‐CARD (ASC), which is critical for stress‐induced depressive behavior and promotes AD phenotypes. Indeed, ASC specks promote Aβ aggregation, presenting both intracellular and extracellular prionoid activities.MethodWe developed a platform for the discovery of new anti‐inflammasome drugs. We modeled the target and performed a chemical library. We validated in‐vitro, using murine primary microglial cultures, the ability of the hits from the screening to inhibit NLRP3 and NLRC4‐mediated IL‐1β production. We further characterized the most potent inhibitors, studying their ability to inhibit processes downstream of inflammasome activation. Thus, we evaluated whether our compounds inhibit ASC oligomerization using fluorescently tagged‐ASC murine macrophages, and we determined their anti‐pyroptotic effect. Finally, we analyzed the ability of a lead compound to reduce neuroinflammation in the brain of LPS injected mice.ResultWe built a 3D homology model for NLRP3 that provides an accurate description of the active site. Through computational screening, we identified 100 hits. The 20% of the hits inhibited NLRP3 in‐vitro, and six among them reduced the activity of the inflammasome below 80%. The three most potent compounds presented IC50 values, for NLRP3‐mediated IL‐1β secretion, in the low micromolar range (9.24, 8.26, and 3.5 μM). Among them, we selected the third one, C77, to characterize it further. C77 inhibited NLRP3 at the protein level, being its IC50 for the ATPase activity 40 nM. Interestingly, C77 inhibited NLRC4 with similar potency, as well as processes downstream of both inflammasomes. Noticeable, C77 inhibited ASC specks formation in response to the stress alarmin HMGB1, at concentrations as low as 10 nM. Finally, C77 also reduced IL‐1β in the brain of mice LPS‐injected.ConclusionWe developed a platform to identify and characterize new AD drugs, targeting neuroinflammation, and using this methodology to identify a lead compound. Future experiments will demonstrate the beneficial effect of our lead compound in AD murine models.
Nutrition status and eating habits of patients with mild cognitive impairment (MCI) or Alzheimer’s dementia (AD)
Authors: Cussigh Barbara , Rakusa Martin 
Published: December 2020

AbstractBackgroundThe purpose of the study was to determine the eating habits of patients with MCI or AD and to determine their nutritional status.Methodspatients with MCI or AD were recruited in the dementia outpatient clinic. Cognitive status and nutritional status were evaluated. Each patient or his/her caregiver fill out full Mini Nutritional Assessment scale (MNA). Maximal score on MNA was 30, patients at risk of malnutrition scored between 17 and 23.5. Patients with less than 17 were considered malnourished. Descriptive statistic for age, body mass index (BMI), arm/calf circumference and total MNA score was performed. MNA score was compared between MCI, mild and moderate AD group using one‐way Anova, and the correlation between the degree of cognitive impairment and MNA score was performed.ResultsMean age of all patients was 74 years (10 years SD), mean MNA score was 24.6 (SD 3.2). The results showed that patients do not consume enough of the recommended nutrients, especially proteins, fruits and vegetables, daily. Measurements of the median circumference of the forearm and calf revealed that more than (60%) patients had decreased muscle mass, although the Body Mass Index was in the normal range in more than 90% of patients. Six patients had moderate, 34 had mild AD, and 38 had MCI. Only one patient was malnourished, while 23 (29.5%) were at risk of malnutrition. All patient with MCI had normal MNA score. Patients with moderate AD had significantly lower MNA score than patients with MCI (21.5, SD 4 vs 25.5 SD 3.4). No differences were found between other groups. A significant correlation was found between cognitive impairment and MNA (r=0.31, p<0.001)ConclusionOur results suggest that patients with AD need nutritional assessment, especially in the advanced phase. It would be worthwhile to make a nutritional assessment at the first and every subsequent visit of the patient to the outpatient clinic to monitor his or her nutritional status.