bluuebunny/crossref_metadata_2025_split huggingface dataset:
A single‐ and multiple‐ascending dose study to evaluate the safety and pharmacokinetics of oral PU‐AD, an epichaperome inhibitor to treat Alzheimer’s disease
Authors: Silverman Michael , Wallner Barbara , Key Cassandra , Duggan Susan M. , Reynolds Laurie 
Published: December 2020

AbstractBackgroundBreakdown of regulatory pathways designed to prevent aggregation and accumulation of disease‐associated proteins contributes to or causes Alzheimer’s Disease (AD). Under these conditions epichaperomes form and take control of pathological pathways. PU‐AD is a small‐molecule, orally bioavailable inhibitor specific to epichaperomes with little or no effect on normal cells, and has shown dramatic beneficial effects in animal models of AD. We describe the first‐in‐man trial of PU‐AD.ObjectivesThis Phase 1, double‐blind, placebo‐controlled, single and multiple‐ascending dose study evaluated the safety and pharmacokinetics (PK) of single and multiple doses of oral PU‐AD.MethodsCohorts of 8 subjects were randomly assigned to active treatment or placebo in a 6:2 ratio. Single doses of oral PU‐AD were 10 mg, 20 mg, and 30 mg in healthy subjects ages 18‐60 years, and daily doses of 20 mg and 30 mg daily for 7 days in healthy subjects >59 years old. Safety was evaluated through observation of adverse event incidence and severity; and changes from baseline in clinical laboratory test results, vital signs, physical examinations, or electrocardiogram results. Plasma PK parameters of PU‐AD were determined, and cerebrospinal fluid (CSF) was sampled for PU‐AD concentration and for biomarkers of neurodegenerative disease in the multiple‐dose cohorts.ResultsPU‐AD was well‐tolerated, with an adverse event profile comparable to that of placebo. No adverse events were serious, severe, or led to withdrawal of dosing. Additionally, there were no other clinically significant safety findings to report. PK was dose‐proportional between 10 mg to 30 mg and showed minimal accumulation with repeated dosing. CSF analyses will be presented.ConclusionPU‐AD, a novel and selective epichaperome inhibitor shown to be efficacious in animal AD models, warrants further evaluation in an AD population. This first‐in‐man trial demonstrated that PU‐AD is well‐tolerated, has favorable plasma PK and CSF exposure, and is a candidate for advancement into Phase 2A trials in AD populations to evaluate target engagement and pharmacological effects.
Relation between alpha‐synuclein and core CSF biomarkers in Alzheimer's disease
Authors: Monge‐Argilés José Antonio , García‐Ayllón María‐Salud , García Victoria Monge , Rueda Francisco Navarrete , Robles Jorge Manzanares , Gasparini‐Berenguer Ruth , Leiva‐Santana Carlos , Romero‐Lorenzo Raquel , Sáez‐Valero Javier 
Published: December 2020

AbstractBackgroundUp to 50% of Alzheimer´s disease (AD) cases exhibit significant Lewy bodies (LB) pathology in addition to plaques and tangles. It has been hypothesized that Aβ, tau and alpha‐synuclein (α‐syn) proteins promote the accumulation of one another. We evaluated the relation between those CSF proteins in a well‐characterized patient mild cognitive impairment (MCI) cohort.MethodBetween 2010‐2015, we included 81 MCI patients (Petersen criteria 2006) from the out‐patient consultation of Neurology Service in University General Hospital of Alicante and 18 control subjects. After a long term follow‐up (mean: 53 months), 25 patients were diagnosed with stable MCI, 32 MCI due to AD (MCI‐AD) and 24 MCI due to Lewy body dementia (MCI‐LBD). Levels of central core AD‐CSF biomarkers Aβ1‐42 (Aβ42), T‐tau (total‐tau) and P‐tau [phospho‐tau (181P)] were measured using ELISA (Innotest, Innogenetics/Fujirebio). Determination of α‐syn levels in CSF were performed using the LEGEND MAXTM human α‐synuclein ELISA kit (BioLegend, San Diego, USA). Rho of Spearman correlation coefficients among CSF protein levels were evaluated.ResultCSF α‐syn significantly positively correlated with T‐tau (Rho= 0.41, p=0.17 ) and P‐tau (Rho=0.57, p=0.001) exclusively for MCI‐AD patients. As expected, the tau proteins significantly positively correlated between them in every patient ΄s group and control subjects. No other significant correlations were found.ConclusionThe exclusive correlation between CSF α‐syn and tau protein levels in MCI‐AD patients, support a pathophysiologic connection between the metabolisms of these proteins, even at the early stages of the illness. In our opinion, the role of α‐syn should be included into the new pathogenetic theories of AD.
The association between overall social support availability and memory by age and sex: An analysis of the Canadian Longitudinal Study on Aging
Authors: Ohman Avery Arres , Maxwell Colleen J , Tyas Suzanne L , Oremus Mark 
Published: December 2020

AbstractBackgroundAccompanying rapidly aging populations is an increase in the prevalence of age‐related memory decline. Modifiable factors such as social support availability (SSA) are important to study because they may affect memory function. However, the impact of SSA on memory may vary by sex or age, and evidence on the topic has not been gathered from large‐scale, population‐based studies of middle‐ and older‐aged adults. This cross‐sectional study explores whether the association between overall SSA and memory differs by sex or age group in 45‐ to 85‐year old persons recruited into the Canadian Longitudinal Study on Aging (CLSA).MethodThe Comprehensive Cohort of the CLSA (n=30,097) is comprised of adults recruited within 25‐50 kilometers of 11 urban centres across Canada. We used multiple linear regression to explore the association between memory (measured using the Rey Auditory Verbal Learning Test immediate [REY I] and delayed recall [REY II]) and SSA (measured using the 19‐item Medical Outcomes Survey‐Social Support Survey), controlling for sociodemographic, health‐related, and health behaviour covariates. The analyses incorporated the CLSA’s weight and strata variables to account for the complex sampling design. We built separate models by age group (45‐54, 55‐64, 65‐74 and ≥75 years) and sex (males, females) to assess effect modification.ResultResults demonstrated positive associations between SSA and memory. For sex, the regression coefficients (β) were larger for males versus females: REY I (β 0.09, 95% confidence interval [CI] 0.06‐0.12; β 0.06, 95% CI 0.03‐0.09, for males and females, respectively); REY II (β 0.07, 95% CI 0.03‐0.10; β 0.03, 95% CI 0.00‐0.07, for males and females, respectively). The strongest associations by age were observed in the 65‐74 age group for REY I (β 0.08, 95% CI 0.04‐0.12) and the 45‐54 age group for REY II (β 0.07, 95% CI 0.02‐0.11).ConclusionResults indicate that individuals with higher levels of SSA might have better memory function, with larger effects observed in males versus females, and varying effects observed by age group. This research points to subgroups that may benefit optimally from social support initiatives developed to promote healthy cognitive function.
The effect of APOE ɛ2/ɛ4 genotype on the incidence of Alzheimer's disease (AD) and mild cognitive impairment (MCI) in African Americans
Authors: Ren Dianxu , Lopez Oscar L. , Lingler Jennifer , Conley Yvette 
Published: December 2020

AbstractBackgroundThe APOE Ɛ2Ɛ4 genotype has been recently reported to associate with increased risk of AD and MCI among non‐Latino whites besides the effects of increased risk of Ɛ4 allele (Ɛ3Ɛ4, Ɛ4Ɛ4). However, there was no study to date on the effects of the Ɛ2Ɛ4 genotype among African American population. The purpose of this study was to examine the associations of APOE Ɛ2Ɛ4 with incident AD dementia and incident of Mild Cognitive Impairment (MCI) among African Americans using the large national dataset from National Alzheimer’s Coordinating Center (NACC).MethodsWe used NACC dataset from 2005 to September 2019 and restricted our analysis to subjects who were African Americans, had an APOE genotype available, first visit with dementia free for AD cohort and both dementia and MCI free for MCI cohort, had a minimum of one follow‐up visit. The subjects were classified into 4 groups based on APOE genotyping: Ɛ2Ɛ4, Ɛ2 (Ɛ2Ɛ2, Ɛ2Ɛ3), Ɛ4 (Ɛ4Ɛ4, Ɛ3Ɛ4), with Ɛ3Ɛ3 carriers serving as the reference group. Cox proportional hazard models were performed to examine the associations of APOE Ɛ2Ɛ4 with incident AD and MCI respectively after controlling age, gender, education, baseline cognitive status and year of initial visit. Adjusted hazard ratio (aHR) and 95% confidence interval (CI) were reported.ResultsAmong AD cohort (N = 2,007), Ɛ2Ɛ4 accounted for 4.9%, Ɛ2/2 and Ɛ2/3 15%, Ɛ3/4 and Ɛ4/4 34.3%, and Ɛ3Ɛ3 45.8%. Over an average of 4.6 years follow‐up, 216 (10.8%) developed AD dementia with the range from 6.3% to 15.7% across 4 groups. Comparing to Ɛ3Ɛ3 carriers, Ɛ2Ɛ4 carriers had a similar risk of incident AD (7.1% vs 8.9%; aHR = 0.85, 95% CI (0.39, 1.84), P = 0.679). Among MCI cohort (N = 1,480), the average follow‐up was 4.5 years and 336 (22.7%) developed MCI with the range from 20.8% to 26.5% across 4 groups. Comparing to Ɛ3Ɛ3 carriers, Ɛ2Ɛ4 carriers had a similar risk of incident MCI (21.1% vs 20.8%; aHR = 0.88, 95% CI (0.51, 1.50), P = 0.637).ConclusionsUnlike the effects on non‐Latino whites, APOE Ɛ2Ɛ4 genotype is not associated with the increased risk of AD and MCI among African Americans.
Cross‐sectional differences in symptomatic presentation and cognitive performance among participants with LATE‐NC compared to FTLD‐TDP
Authors: Teylan Merilee , Mock Charles , Gauthreaux Kathryn , Culhane Jessica E. , Chen Yen‐Chi , Chan Kwun Chuen Gary , Kukull Walter A. , Nelson Peter T , Katsumata Yuriko 
Published: December 2020

AbstractBackgroundTransactive response DNA‐binding protein 43 (TDP‐43) is misfolded and aberrantly phosphorylated in FTLD‐TDP. It is also the key proteinopathic feature in limbic‐predominant age‐related TDP‐43 encephalopathy neuropathologic change (LATE‐NC). There has been some controversy as to the similarities and differences between FTLD‐TDP and LATE. We examined how the symptomatic presentation and cognitive performance compare between autopsy‐confirmed LATE‐NC and FTLD‐TDP.MethodParticipants with LATE‐NC or FTLD‐TDP were identified at autopsy using data from the National Alzheimer’s Coordinating Center Neuropathology Data Set v10. Participants were excluded if they had other rare neuropathologic diseases or had their last clinic visit greater than 36 months from their date of death. Presence of cognitive, behavioral, and motor symptoms were compared among those with a dementia diagnosis at their last visit. Linear regression analyses with generalized estimating equations were run to test for mean differences between the two groups on five cognitive domain z‐scores (episodic memory, attention/working memory, executive function, semantic memory, global composite score) calculated from neuropsychological test scores at their last visit. Models were stratified based on global CDR score (CDR=0.5‐1, 2‐3) and adjusted for neuropsychological test battery, age at death, sex, years of education, Alzheimer’s disease neuropathologic change, presence of Lewy bodies, and presence of microinfarcts.ResultWe identified 233 LATE‐NC and 86 FTLD‐TDP participants. LATE‐NC participants were older at death and more likely to be an APOE ε4 carrier than those with FTLD‐TDP. Dementia participants with LATE‐NC were less likely to demonstrate language impairment, apathy, disinhibition, and personality changes, but were more likely to have visuospatial impairments, visual hallucinations, and delusions compared to FTLD‐TDP participants. Examining the differences in mean cognitive domain z‐scores, participants with LATE‐NC and a global CDR score of 0.5‐1 performed significantly better in the language domain compared to those with FTLD‐TDP. Significant differences in mean z‐scores were not observed among other cognitive domains, or among participants with a global CDR score of 2‐3.ConclusionIn this sample, there were symptomatic differences between LATE‐NC and FTLD‐TDP among participants with dementia. Difference in the language domain could be detected in mild stages of impairment through neuropsychological test scores.
Whole brain generative model identifies neurotransmitter alterations underlying Alzheimer's disease progression
Authors: Khan Ahmed F , Palomero‐Gallagher Nicola , Zilles Karl , Medina Yasser Iturria 
Published: December 2020

AbstractBackgroundAlzheimer’s disease (AD) involves heterogeneous aberrations in multiple biological processes, although their causal molecular mechanisms are not fully understood. As the primary neuronal signalling molecules, neurotransmitters regulate a variety of biological processes pathological in AD, such as the coupling between neural activity and vascular response. However, due to the infeasibility of mapping most neurotransmitters in‐vivo, alterations during disease progression are not well characterized. We propose multi‐modal, subject‐specific models of neuroimaging alterations as functions of local neurotransmitter concentrations, which we combine with clinical data to identify specific neurotransmitters prominently altered during AD progression.Method(1) We used the methods described in [Iturria‐Medina et al., Neuroimage, 152:60–77, 2017] to pre‐process longitudinal neuroimaging data (amyloid β and tau protein distributions, cerebral blood flow, r‐fMRI, glucose metabolism, and grey matter density) for 141 healthy and 302 diseased subjects from ADNI. (2) Using the densities of 15 neurotransmitter receptors from multiple cortical areas [Palomero‐Gallagher & Zilles, Neuroimage, 197:716–741, 2019] and 4 serotonin‐type PET templates [Lanzenberger et al., Biological psychiatry, 61(9):1081–1089, 2007], we built subject‐specific, generative models of changes in neuroimaging in terms of (i) other neuroimaging modalities, (ii) network propagation, and (iii) first‐order receptor‐moderated interactions. (3) By evaluating the monotonicity of receptor‐associated coefficients with aging‐related cognitive measures (memory performance, executive function, MMSE, CDR, and ADAS), we identified receptors with a significant causal role in AD progression.ResultNotably, the model explains 50%‐77% of observed variance in all imaging bio‐markers across clinical groups (HC, EMCI, LMCI, AD). Significant receptor‐imaging interactions with AD progression were identified for (i) NMDA and cholinergic receptors for amyloid distribution, (ii) nicotinic acetylcholine and serotonergic receptors for tau distribution, (iii) glutamatergic NMDA and D1 dopaminergic receptors for blood flow, (iv) GABAergic, cholinergic, dopaminergic and serotonergic receptors for neural activity, (v) GABA receptors for glucose metabolism, and (vi) GABAergic and serotonergic receptors for gray matter density.ConclusionA generative, multi‐modal neuroimaging model including 19 receptors allowed, for the first time, the in‐vivo identification of receptor alterations underlying AD progression and its associated cognitive/clinical deterioration. Critically, identified receptors are significant molecular controllers of typical multi‐modal alterations in AD (including tau and amyloid accumulation, vascular dysregulation, and extended brain atrophy).
Effects of azeliragon on ADAS‐cog and CDR domains and individual items in patients with mild Alzheimer's disease and type 2 diabetes (T2D)
Authors: Burstein Aaron H. , Dunn Imogene , Gooch Ann M. , Valcarce Carmen 
Published: December 2020

AbstractBackgroundAzeliragon, an oral antagonist of the receptor for advanced glycation endproducts (RAGE), was evaluated in an 18‐month Phase 3 study as a treatment for patients with mild Alzheimer’s disease (AD) (the STEADFAST Study). Post‐hoc analyses in a T2D subgroup (HbA1c ≥ 6.5%) found that azeliragon‐treated patients exhibited less cognitive decline (ADAS‐cog11), less whole brain atrophy, less hippocampal atrophy, less ventricular enlargement, and reduced plasma inflammatory cytokine concentrations compared to patients treated with placebo. The current retrospective exploratory analysis was performed to evaluate ADAS‐cog and CDR symptom domains and individual test items to ascertain which were sensitive to treatment effects.MethodSTEADFAST was a randomized, double‐blind, placebo‐controlled trial in 875 patients with probable mild AD (MMSE 21‐26, CDR global 0.5‐1) receiving stable acetylcholinesterase inhibitors and/or memantine, evaluating the efficacy and safety of 18 months of treatment with azeliragon 5 mg/day relative to placebo. STEADFAST included two separate studies (A‐Study completed as planned, B‐Study prematurely terminated following negative results from the A‐Study) under a single protocol. Patients in the A‐Study with T2D (HbA1c ≥ 6.5%) were analyzed with mean changes from baseline calculated for ADAS‐cog11 and CDR individual item and symptom domain scores. Standard effects sizes were determined using Cohen d. Treatment differences in Month 18 change from baseline were evaluated using both t‐test (presented herein) and Wilcoxon test.ResultForty‐seven patients (26 azeliragon, 21 placebo of whom 19 and 17 had Month 18 data) were analyzed. ADAS‐cog Language and Praxis domains were nominally significantly different favoring azeliragon (p=0.01 and p=0.049, respectively) with Cohen d values of 0.86 and 0.66. A trend for less decline in the Memory domain (p=0.07, effect size 0.62) was noted. No significant differences were noted on CDR cognitive or functional domains. Nominal significant differences favoring azeliragon were noted for ADAS‐cog comprehension (p=0.005, effect size 0.99), ideational praxis (p=0.012, effect size 0.84) and spoken language (p=0.067, effect size 0.62) items and the CDR Memory item (p=0.032, effect size 0.73).ConclusionResults suggest that azeliragon may have benefits over placebo with less decline in memory, language, and praxis over 18 months in patients with mild AD and T2D.
Specific signatures of circulating extracellular vesicles emerged as novel biological tools for the detection of biomarkers for MCI and Alzheimer's disease
Authors: Ramassamy Charles 
Published: December 2020

AbstractBackgroundAlzheimer’s disease (AD) is characterized by a series of overlapping pathophysiological cascades, including the aggregation of β‐amyloid plaques and the formation of neurofibrillary tangles derived from hyperphosphorylated tau proteins. Actually, the search for peripheral biomarkers for AD that reflect AD‐related processes in the brain has received considerable attention but the clinical utility of blood‐based biomarkers is not validated. Accumulating evidence supports the central role of exosomes or extracellular vesicles (EVs) in the pathophysiology of AD. In the brain, they can act as vehicles for the cell‐to‐cell transfer of the AD pathogenic proteins. Our objectives were to demonstrate that some proteins cargo in the circulating EVs represent a great potential in harbor disease‐specific molecular signatures of brain disorders, making them an ideal source of biomarkers.MethodWe have isolated EVs from plasma (pEVs) of control, MCI and AD subjects at different stages of the disease (mild, moderate, severe). Then, their size, shape and density were characterized by transmission electronic microscopy and nanoparticles tracking analysis (NTA). The presence of pEVs specific proteins TSG101, CD63, GAPDH were confirmed by Western Blot and AD‐related proteins were quantified by Luminex assay.ResultOur data showed that the levels of these proteins were higher in pEVs than in plasma indicating that the pEVs represent a sensitive tool to screen peripheral biomarkers. We observed a reduction of tTau in pEVs from MCI subjects while the APP concentration was reduced in pEVs from MCI and early AD. Interestingly, pTau‐T181 and APP concentrations in pEVs were correlated with cognitive performances (MMSE , MoCA). Aβ42 and pTau‐T181 levels in pEVs were unchanged in MCI but elevated in moderate AD patients compared to controls. Abnormal levels of APP and pTau‐T181/tTau ratio in pEVs levels demonstrated good accuracy to define MCI and AD staging.ConclusionTaken together, these results demonstrated that the identification of these proteins in pEVs could have great implication in differentiating MCI individuals to AD patients and to monitor the disease progression. This work was supported by the Chaire Louise & André on Alzheimer’s disease, Foundation Armand‐Frappier (CR) and CIHR grant (TF).
Differences in structural and functional DMN connectivity in amyloid‐positive AMCI who converted to AD dementia
Authors: Balthazar Marcio Luiz Figueredo , Magalhaes Thamires Naela Cardoso , Rezende Thiago Junqueira Ribeiro , de Campos Brunno , Ramalho Luciana , Joaquim Helena Passarelli Giroud , Talib Leda Leme , Forlenza Orestes Vicente , Cendes Fernando 
Published: December 2020

AbstractBackgroundDefault Mode Network (DMN) has emerged as a potential biomarker of Alzheimer’s disease (AD), but it is not clear if it can differentiate amnestic mild cognitive impairment (aMCI) in the spectrum of AD (with altered amyloid‐ aMCI‐Aβ+) who will evolve to dementia.Methods34 aMCI subjects with evidence of AD pathophysiology (low Aβ42 < 540 pg/mL) were followed for a median of 13 months. All subjects had CDR score of 0.5 (with an obligatory memory score of 0.5), poor performance on RAVLT, considering age and education and Fazekas Scale 0 or 1. White Matter (WM) microstructure was evaluated by diffusion tensor imaging ‐ DTI MultiAtlas; FC by UF2C; HV by Freesurfer softwares. We considered conversion from aMCI to AD dementia if CDR score changed from 0.5 to 1. We performed MANOVAs to differentiate the groups, considering age and time of reevaluation as covariables. Afterwards, we analyzed ROC curves with the variables that were significantly different between the groups.ResultsWe found 8/34 converters (23.5%). Converters were older (p=0.049), but no other differences were found regarding sex, education, time of reevaluation and global cognitive performance in the first evaluation between the groups. aMCI‐Aβ+ converters had higher levels of tau (p=0.035), p‐tau (p=0.011) and a tendency to have smaller right HV (p=0.07). We did not find any significant result concerning DMN FC. However, we found that right cingulum parahippocampal bundle radial diffusivity was higher in aMCI‐Aβ+ converters (p=0.017), indicating myelinic dysfunction. Regarding ROC curve analyses, all significant variables showed moderate diagnostic accuracy: right cingulum parahippocampal bundle (AUC = 0.806), t‐tau (AUC = 0.788) and p‐tau (AUC = 0.706).ConclusionWe found that structural (right parahippocampal cingulum bundle) but not functional DMN connectivity alterations may differentiate aMCI‐Aβ+ subjects who converted to AD dementia.