bluuebunny/crossref_metadata_2025_split huggingface dataset:
Spatial Engineering Direct Cooperativity between Binding Sites for Uranium Sequestration
Authors: Sun Qi , Song Yanpei , Aguila Briana , Ivanov Aleksandr S. , Bryantsev Vyacheslav S. , Ma Shengqian 
Published: December 2020

AbstractPreorganization is a basic design principle used by nature that allows for synergistic pathways to be expressed. Herein, a full account of the conceptual and experimental development from randomly distributed functionalities to a convergent arrangement that facilitates cooperative binding is given, thus conferring exceptional affinity toward the analyte of interest. The resulting material with chelating groups populated adjacently in a spatially locked manner displays up to two orders of magnitude improvement compared to a random and isolated manner using uranium sequestration as a model application. This adsorbent shows exceptional extraction efficiencies, capable of reducing the uranium concentration from 5 ppm to less than 1 ppb within 10 min, even though the system is permeated with high concentrations of competing ions. The efficiency is further supported by its ability to extract uranium from seawater with an uptake capability of 5.01 mg g−1, placing it among the highest‐capacity seawater uranium extraction materials described to date. The concept presented here uncovers a new paradigm in the design of efficient sorbent materials by manipulating the spatial distribution to amplify the cooperation of functions.
Periodontal pathogens and their association with incident all‐cause and Alzheimer’s disease dementia in a large national survey
Authors: Beydoun May A , Beydoun Hind A , Hossain Sharmin A , El‐Hajj Ziad W , Weiss Jordan , Zonderman Alan 
Published: December 2020

AbstractBackgroundInfectious agents including periodontal pathogens have recently appeared as important actors in Alzheimer’s Disease (AD) pathology. We examined associations of serum immunoglobulin G (IgG) against periodontal pathogens and Pd markers with incident all‐cause and AD dementia as well as AD mortality among U.S. middle‐aged and older adults.MethodPeriodontal disease (Pd) markers [Clinical Attachment Loss (CAL); probing depth and periodontal pathogen immunoglobulin G (IgG)] were investigated in relation to AD and all‐cause dementia incidence and to AD mortality, using data from the third National Health and Nutrition Examination Surveys (NHANES III, 1988‐1994) linked longitudinally with National Death Index and Medicare data through January 1st, 2014, with up to 26y of follow‐up. Sex‐ and age group‐specific multivariable‐adjusted Cox proportional hazards models were conducted.ResultAmong those ≥65y, AD incidence and mortality were consistently associated with probing depth, two factors and one cluster comprised of IgG titers against Porphyromonas gingivalis (Pg), Prevotella melaninogenica (Pm) and Campylobacter rectus (Cr) among others. Specifically, AD incidence was linked to a composite of Cr and Pg titers (per SD, aHR=1.22; 95% CI, 1.04‐1.43, P=0.012), while AD mortality risk was increased with another composite (per SD, aHR=1.46; 95% CI, 1.09‐1.96, P=0.017) loading highly on Pg, Prevotella intermedia, Prevotella nigrescens, Fusobacterium nucleatum, Cr, Streptococcus intermedius, Capnocylophaga Ochracea and Pm.ConclusionThis study provides evidence for an association between periodontal pathogens and AD, which was stronger for older adults. Effectiveness of periodontal pathogen treatment on reducing sequelae of neurodegeneration should be tested in randomized controlled trials.
Lower CSF amyloid level is associated with sooner anti‐psychotic use in Alzheimer disease: A survival analysis
Authors: Cahan Joshua Gabriel , Bonakdarpour Borna 
Published: December 2020

AbstractBackgroundBehavioral and psychological symptoms of dementia (BPSD) are a common feature of Alzheimer disease (AD). Antipsychotics (AP) remain a mainstay of BPSD treatment but have serious adverse effects and may serve as a proxy for BPSD in retrospective studies. Alzheimer biomarkers have been associated with neuropsychiatric symptoms and risk of post‐operative delirium. Potential associations between CSF markers of Alzheimer disease and antipsychotic use have not been explored. Here we used a survival analysis approach to probe the relationship between CSF AD biomarkers and BPSD by looking at AP use.MethodA retrospective cohort of 86 patients(average 72 y/o +/‐5, 46.5 %M) over the age of 65 with AD confirmed on CSF testing between December 2010 and March 2018 and no premorbid primary psychiatric diagnosis was identified using Northwestern Memorial Hospital’s Enterprise Data Warehouse. Patients were stratified by levels of amyloid‐Beta 42(AB42), phosphorylated tau, total tau, and amyloid to tau index(ATI) with a median split. We looked at time‐to‐AP use for each group using a Kaplan‐Meier analysis. A log rank test was used to calculate statistical significance. Chi‐square was used to compare nominal and Mann‐Whitney U for quantitative features of each group.ResultAltogether 11 patients received APs following CSF testing. There was no difference in AP use if groups were stratified by total tau, phosphorylated tau, or ATI. Nine (20.0%) of patients in the lower AB42 group compared with only 2 (4.5%) in the higher AB42 group received an AP. Patients in the lower AB42 group had sooner time‐to‐AP use on Kaplan‐Meier analysis, confirmed with a log‐rank test (p=0.04) (Figure 1). Comparing the two groups of 43 patients stratified by AB42 level, we did not detect a significant difference in demographics, MMSE scores, AD specific medication use, and comorbidities by the Charlson Comorbidity Index (Table 1).ConclusionThese results suggest a relationship between lower CSF amyloid levels and sooner AP use. This study supports prior work showing a relationship between amyloid deposition on PET imaging and neuropsychiatric symptoms. CSF AB42 appears important towards developing a biological framework of neuropsychiatric symptoms in Alzheimer dementia and may help with BPSD prognostication.
The 23‐pneumococcal polysaccharide vaccine (PPV23) importance in an Alzheimer’s community from the south of Brazil
Authors: Nakakogue Lindsey Mitie , Baena Cristina Pellegrino , Sacchi Beatriz Chiquito , Cotrim Ivana de Oliveira , dos Santos Vitória Karoline Justino 
Published: December 2020

AbstractBackgroundPneumonia is the leading cause of death in Alzheimer's patients. The importance of PPV23 on this population is unknown.Method510 patients diagnosed with Alzheimer's Disease or Mixed Dementia treated at a public outpatient clinic in Londrina ‐ Paraná‐ Brazil, from January 1, 2015 to December 31, 2018 were selected. The following data were collected: gender, age, education, type of dementia, dementia classification by Clinical Dementia Rating, degree of functionality for basic activities (Katz), evolution of the Mini Mental State Examination in the period, Body Mass Index, incidence of delirium symptoms (agitation and aggression), date of vaccination with PPV23, Pneumococcal Conjugate Vaccine 13 (PCV13) and Influenza, if living in nursing home, presence of comorbidities such as stroke, myocardial infarction, hypertension, diabetes, chronic lung disease, chronic renal failure or immunosuppressive disease, if they were alcoholics or smokers and if they had diagnosis, hospitalization or death from pneumonia or other causes. Means were compared between groups by Student's t test and the proportions by Fisher's exact test. Logistic regression models were created to test the association between vaccination and outcomes, with adjustment for confounding factors.ResultThe sample consisted of 510 elderly, 65% women, 53.5% with 1‐4 years of schooling. The predominant age group was 80‐89 years (47.3%), 88% had a diagnosis of AD and most was CDR I (47%), ie mild dementia. Less than half (46.5%) were vaccinated with PPV23. There was no significant association between vaccination with PPV23 and the risk of pneumonia or death. Vaccination was associated with a higher risk of hospitalization for pneumonia (p 0.045), however, this association disappears with adjustment for age and CDR.ConclusionThis study didn’t found difference for diagnosis or hospitalization for pneumonia between vaccinated and non‐vaccinated patients. Future studies should explore the causes, contributing factors and impact of pneumonia prevention in this elderly population with dementia.
Effect of cumulative exposure to psychosocial stressors at work on global cognitive function: A 25‐year longitudinal study
Authors: Duchaine Caroline S , Brisson Chantal , Talbot Denis , Gilbert‐Ouimet Mahée , Trudel Xavier , Vézina Michel , Diorio Caroline , Giguère Yves , Milot Alain , Laurin Danielle 
Published: December 2020

AbstractBackgroundBy 2050, an estimated 152 million people will be living with dementia. Prospective studies suggest that exposure to psychosocial stressors at work could be associated with a higher risk of mild cognitive impairment or dementia, but the evidence is still not clear.MethodThis study aimed to evaluate the effect of cumulative exposure to psychosocial stressors at work on global cognitive function in a cohort followed for over 25 years. At baseline in 1991‐1993 (T1), 9,188 white‐collar workers were recruited. Two follow‐ups were carried out in 1999‐2001 (T2) and 2015‐2019 (T3). This analysis was done among 5,728 participants working in T2, which participated in T3. Global cognitive function was evaluated with the validated Montreal Cognitive Assessment test (Nasreddine, 2005) and categorized in three groups according to standardized cut‐offs. Psychosocial stressors at work were evaluated with the validated Job Content Questionnaire (Karasek, 1979) at each time. The effect of cumulative exposure to psychosocial stressors at work at T1 and T2 on cognitive function categories at T3 was estimated with marginal structural models using inverse probability of treatment and censoring weights. Each observation was weighted for the inverse of the probability of death and lost to follow‐up and adjusted for potential confounders measured at T1 (age, sex, education, number of years in the same job, comorbidities, and lifestyle habits). Multiple imputation of missing data was performed.ResultWorkers exposed to low job demand and those exposed to a passive job (low job demand combined with low job control) at both T1 and T2 were at higher risk of moderate to severe cognitive impairment than non‐exposed workers (prevalence ratios (PR) and 95% confidence intervals (CI) of 1.34 (1.10;1.63), p=0.003, and 1.27 (1.05;1.54), p=0.012 respectively). Men, but not women, exposed to low job control at both T1 and T2 were at higher risk of moderate to severe cognitive impairment than non‐exposed workers (PR and 95% CI: 1.38 (1.07;1.79), p=0.015). No statistically significant associations were observed with the risk of mild cognitive impairment.ConclusionPrimary prevention of cognitive impairment could be possible with the reduction of these frequent and modifiable psychosocial stressors at work.
Oral immunization with soybean storage protein containing amyloid β4‐10 prevents spatial learning decline
Authors: Kawarabayashi Takeshi , Nakamura Takumi , Takatama Masamitsu , Shoji Mikio 
Published: December 2020

AbstractBackgroundAmyloid‐β protein (Aβ) plays a central role in the pathogenesis of Alzheimer’s disease (AD). Because AD pathologies begin two decades before the onset of dementia, prevention of Aβ amyloidosis has been proposed as a mean to block the pathological cascade. We generated a transgenic plant‐based vaccine, a soybean storage protein containing Aβ4‐10, named Aβ+, for oral Aβ immunization.MethodOne mg of Aβ+ or control protein (Aβ‐) with 10 mg cholera toxin subunit B was orally administered via a catheter to TgCRND8 mice once a week from 9 weeks. Extended Morris water maze tests for 10 consecutive days were examined every 4 weeks. Mice were analyzed at 23 weeks (Aβ+ n = 9, Aβ– n = 11), 43 weeks (Aβ+ n = 7, Aβ– n = 6), and 59 weeks (Aβ+ n = 6, Aβ– n = 7).ResultAβ+ immunization raised both anti‐Aβ antibodies and cellular immune responses. Plasma from Aβ+ treated mice showed staining of Aβ oligomers. Spatial learning decline was prevented in the Aβ+ immunized group from 21 weeks. In Tris‐buffered saline (TBS), sodium dodecyl sulfate (SDS), and formic acid (FA) serial extractions, all sets of Aβ species from Aβ monomer, low to high molecular weight Aβ oligomers, and Aβ smears had different solubility in TgCRND8 brains. Aβ oligomers decreased in TBS fractions, corresponding to an increase in high molecular weight Aβ oligomers in SDS extracts and Aβ smears in FA fraction of the Aβ+ treated group. There was significant inhibition of histological Aβ burden, especially in diffuse plaques, and suppression of microglial inflammation. Processing of amyloid‐β protein precursor was not different between Aβ+ and Aβ‐ groups. No evidence of amyloid‐related inflammatory angiopathy was observed.ConclusionAβ+ oral immunization could be a promising, cheap, and long‐term safe disease‐modifying therapy to prevent the pathological process in AD.
A phase II, single center, randomized, double‐blind, placebo‐controlled study of the safety and therapeutic effectiveness of intranasal glulisine in amnestic mild cognitive impairment and probable mild Alzheimer’s disease
Authors: Rosenbloom Michael H. , Barclay Terry R , Erickson Lauren O , Pyle Maria , Green Emily A. , Svitak Aleta , Hage Lyndsay M. , Frey William H. , Hanson Leah R. 
Published: December 2020

AbstractBackgroundIN insulin is a potential treatment for neurodegenerative disease shown to increase cerebral glucose update, reduce amyloid plaques and improve verbal memory in cognitively‐impaired as well as normal adults. Investigations have suggested that rapid‐acting (RA) insulins such as glulisine may result in superior cognitive benefits compared to regular insulin.MethodWe performed a single center, randomized, double‐blind, placebo‐controlled study to evaluate the efficacy of IN glulisine versus placebo in N=35 memory impaired (MCI/AD) subjects. Subjects with non‐insulin dependent diabetes mellitus (NIDDM) were included in the study. IN administration utilized the Impel NeuroPharma I109 Precision Olfactory Delivery (POD®) device. The ADAS‐Cog13, CDR global score, and FAQ were measured at baseline, 3, and 6 months. Secondary outcome measures included digit span forward/backwards, Trailmaking part A/B, COWAT, and WMS logical memory. Depression and suicidality were assessed using the GDS and C‐SSRSResultsSubjects in the saline group were significantly older than those in the saline group (p=0.022). No significant differences in gender, education, ApoE4 status, and MOCA score existed between treatment groups. Overall, the number of adverse events per person was similar between groups (2.32 vs. 2.24, p=0.824); although subjects receiving IN glulisine had higher rates of nasal irritation (25.0% vs 13.9%) and respiratory symptoms (15.9% vs 8.3%) compared to placebo. Glucose<70 was observed in one subject receiving RA insulin, but otherwise, there were no other cases of hypoglycemia, including three NIDDM patients. Insulin levels and blood pressure was unaffected by treatment. No significant difference for ADAS‐Cog 13, CDR‐SOB or FAQ scores were found between treatment groups at 3 and 6 months. There was no impact of IN glulisine on depression or suicidality.ConclusionIN glulisine was safe and well‐tolerated and did not consistently impact peripheral glucose or insulin levels. There were no enhancing effects of IN glulisine on cognition, function, or mood, but the ability to detect significance was limited by number of subjects successfully enrolled and study duration. Additional investigations following a larger MCI/AD cohort inclusive of NIDDM subjects over a longer duration are necessary to better evaluate RA insulin efficacy in this population.
White matter microstructural damage as an early sign of subjective cognitive decline
Authors: Zhao Hui , Luo Cai Mei , Li Chun Meng 
Published: December 2020

AbstractBackgroundSubjective cognitive decline (SCD) is considered a preclinical state of Alzheimer's disease (AD) and may represent a more advanced preclinical status than amnestic mild cognitive impairment (aMCI). Our aim was to explore changes in the white matter (WM) microstructure and their correlation with cognitive function in these AD‐spectrum patients.MethodDiffusion tensor images from 43 individuals with normal cognition (NC), 38 SCD patients and 36 aMCI patients were compared using an atlas‐based segmentation strategy. The correlation between diffusion parameters and cognitive function was further analysed.ResultThe anatomical pattern of WM impairment was generally similar between SCD and aMCI patients. However, aMCI patients showed significantly lower fractional anisotropy (FA) values in corpus callosum (forceps major (Fma) and forceps minor (Fmi)), as well as significantly increased mean diffusivity (MD) in the bilateral anterior thalamic radiation (ATR), left corticospinal tract (CST. L), Fmi, left Cingulum (cingulate gyrus) (CgC. L), left cingulum (hippocampus) (CgH. L), and left inferior fronto‐occipital fasciculus (IFO. L), than those of SCD subjects, indicating a disruption in WM microstructural integrity in the aMCI. Individuals with microstructural disruption in Fmi, CgC. L and CgH. L tracts performed worse in general cognition and memory function tests, as indicated by line regression analysis.ConclusionSCD individuals had extensive WM microstructural damage in a pattern similar to that seen in aMCI, although presenting a cognitive performance comparable to cognitively healthy individuals. Our results suggest that WM integrity might precede objectively measurable memory decline and may be a potential early biomarker for AD.
Age and cognitive diagnosis influence cerebrospinal fluid ketone levels after a triglyceride infusion in older adults
Authors: Hanson Angela J. , Banks William A. , Bettcher Lisa F. , Pepin Robert , Raftery Daniel , Craft Suzanne 
Published: December 2020

AbstractBackgroundKetone bodies and diets which increase plasma ketones are being investigated for treatments for Alzheimer’s disease (AD), but little is known about what influences ketone body levels in the brain.MethodOlder adults (n=21, age 67.7 ± 8.6) underwent a 5‐hour TG and saline infusion on different days in random crossover design; CSF was collected at the end of the infusion. Targeted aqueous metabolites were measured using Shimadzu Nexera 20/AB‐Sciex 6500 Triple Quadrupole Liquid Chromatography‐Mass Spectroscopy which targets 216 metabolites representing over 35 different metabolic pathways. Data were analyzed using MetaboAnalyst 4.0 and SAS.ResultOf 216 possible metabolites, 99 were detectable in the CSF, with an average of 88 metabolites per sample which did not differ by treatment (saline 87.6 ± 1.4, TG 87.7 ± 1.7). Three metabolites significantly differed by treatment: 3‐hydroxybutyrate (HBA), glutamic acid and methylguanosine (Table). The top hit HBA further differed by cognitive diagnosis. Fasting HBA was similar for both groups but TG‐induced increases in HBA were over 3 times higher for those with cognitive impairment (change score normal control 9.8 uM ± 8.3, cog impair 32.4 uM ±7.4, p value log transformed levels 0.0198). None of the metabolites in Table differed by APOE status or by sex. Age positively correlated with fasting HBA whereas systolic blood pressure and fasting glucose positively correlated with TG HBA and HBA change score. Fasting lipid levels did not predict fasting or TG‐induced HBA.ConclusionWe detected metabolites in human CSF, and most metabolites did not change after a TG infusion. The top metabolite was the ketone body HBA, and levels were influenced by age, cognitive diagnosis, and markers of the metabolic syndrome. These results suggest that interventions that increase plasma ketones may lead to higher brain ketones in groups at risk for AD.
In vivo measurement of widespread synaptic loss and associated tau accumulation in early Alzheimer’s disease
Authors: Mecca Adam P. , O'Dell Ryan S. , Chen Ming‐Kai , Naganawa Mika , Toyonaga Takuya , Godek Tyler A. , Harris Joanna E. , Bartlett Hugh H. , Zhao Wenzhen , Gallezot Jean‐Dominique , Nabulsi Nabeel B. , Ropchan Jim R. , Ye Yunpeng , Wyk Brent C. Vander , Arnsten Amy F.T. , Huang Yiyun , Carson Richard E. , van Dyck Christopher H. 
Published: December 2020

AbstractBackgroundUsing [11C]UCB‐J–PET we have shown significant reductions in hippocampal SV2A specific binding as a marker of synaptic density in participants with early Alzheimer’s disease (AD). However, postmortem studies have suggested more widespread neocortical reductions in synaptic density that are associated with fibrillary tau accumulation.MethodsWe measured SV2A binding with [11C]UCB‐J‐PET in 34 participants with early AD (MMSE=23.1±4.1, CDR=0.5‐1.0) and 19 cognitively normal (CN) participants (MMSE=29.3±1.1, CDR=0). Amyloid status was confirmed by [11C]PiB‐PET. For [11C]UCB‐J‐PET, we calculated the distribution volume ratio (DVR) using a cerebellum reference. In a subset of 10 CN and 10 AD participants, we measured tau accumulation using [18F]flortaucipir‐PET. [18F]Flortaucipir standardized uptake value ratios (SUVRs) were calculated using an inferior cerebellum reference.ResultsOur primary analysis of group differences in SV2A binding demonstrated a significant effect of group (F(1,51)=33.4, P<0.00001) and group*region (F(10,510)=2.4, P=0.01) as predictors of SV2A binding (DVR). Post‐hoc comparisons revealed significant group differences in all medial temporal regions and more broadly in neocortical regions (Figure 1). SV2A reductions in AD were most pronounced in the hippocampus (DVR–17.3%, P<0.00001; BP
ND–19.8%) and entorhinal cortex (DVR–15.7%, P<0.00001; BP
ND–17.6%), but also present in parahippocampal, amygdala, lateral temporal, prefrontal, posterior cingulate/precuneus, lateral parietal, and pericentral regions. These reductions were largely maintained after correction for volume loss and were more extensive than decreases in gray matter volume. In a smaller sample of participants with tau PET, AD participants demonstrated significantly higher entorhinal cortical (ERC) [18F]flortaucipir binding compared to CN participants (CN SUVR=1.11±0.12, AD SUVR=1.68±0.16, p<0.00001). ERC‐tau was inversely associated with hippocampal synaptic density (r=‐0.63, P=0.005). Synaptic density and tau were inversely associated in regions of early and later Braak stages (r=‐0.45 to ‐0.59, P<0.05).ConclusionWe observed widespread reductions of synaptic density with [11C]UCB‐J‐PET in medial temporal and neocortical regions in early AD. ERC tau accumulation was associated with lower hippocampal synaptic density. This inverse association may reflect synaptic failure due to tau pathology in ERC neurons projecting to the hippocampus. Further longitudinal studies are needed to elucidate the chronology and topography of tau accumulation and synaptic loss in AD and their relationship.