bluuebunny/crossref_metadata_2025_split huggingface dataset:
Subtle cognitive deficits assessed by means of CANTAB in a cohort of subjects with CSF AD profile
Authors: Chipi Elena , Salvadori Nicola , Montanucci Chiara , Toja Andrea , Siena Elisa , Paoletti Federico Paolini , Bellomo Giovanni , Parnetti Lucilla 
Published: December 2022

AbstractBackgroundIn order to make successful disease‐modifying treatments, it is needed to shift Alzheimer’s disease (AD) diagnosis toward individuals with subtle cognitive deficits not yet fulfilling MCI criteria (pre‐MCI), entity associated with AD biomarkers positivity and increased risk of progression (Parnetti et al.,2019). This might allow to identify the individuals candidate to biomarker assessment. The detection of subtle cognitive impairment is limited by the sensitivity of standard neuropsychological measures (Wolfsgruber et al.,2020; Chipi et al.,2019). Cambridge Neuropsychological Test Automated Battery (CANTAB) represents an advanced computerized tool for the assessment of non‐verbal frontal‐subcortical functioning (Robbins et al.,1994). We aimed to explore the frequency of cerebrospinal fluid (CSF) AD‐like profile in pre‐MCI subjects defined as those obtaining low scores (≥‐1 SD) in at least one CANTAB test.MethodWe retrospectively analyzed 64 consecutive subjects (31 males, 33 females, mean age = 67±7.9) referring to our Memory Clinic for subjective cognitive complaints. All participants performed a comprehensive standard neuropsychological battery, reporting normal scores, and tests from CANTAB (Paired Associated Learning‐PAL; Pattern Recognition Memory‐PRM; Spatial Working Memory‐SWM). Pathological performance at CANTAB (CANTAB+) was defined as scores ≥‐1 SD in at least one task. All of them underwent lumbar puncture for the analysis of CSF core AD biomarkers (Aβ42/Aβ40 ratio, total tau, phospho‐tau). By applying the A/T/(N) classification scheme (Jack et al.,2018), AD CSF profile was defined as A+/T+. As A biomarker, we considered the Aβ42/40 ratio.ResultOut of 64 subjects, 43 performed ≥‐1SD in at least one test from CANTAB. In those 43 CANTAB+ subjects, 10 (23%) were A+/T+, 4 (9%) A+, and 22 (51%) A‐/T‐. Among CANTAB‐ (N = 21), 3 (14%) were A+/T+; 3 (14%) A+; 13 (61%) A‐/T‐. Among CANTAB+ subjects with A+/T+ (N = 10), 8 (80%) showed deficit in PAL, 4 at SWM and none of them showed altered scores at PRM.ConclusionConsistent proportion (23%) of pre‐MCI subjects with at least one altered score at CANTAB showed a CSF pattern compatible with AD. Since PAL test was altered in 80% of these subjects, if confirmed in independent cohorts, it might represent a sensitive neuropsychological measure to identify subjects with subtle cognitive deficits who may deserve CSF analysis for detecting preclinical AD.
A new flortaucipir PET biomarker based on graph theory for early detection of CTE in former American football players
Authors: Protas Hillary D. , Su Yi , Luo Ji , Chen Kewei , Alosco Michael L , Adler Charles , Balcer Laura , Bernick Charles B. , Au Rhoda , Banks Sarah J , Barr William , Coleman Michael J , Dodick David W. , Katz Douglas I , Marek Ken , Mariani Megan , McClean Michael D , McKee Ann C. , Mez Jesse B. , Palmisano Joseph , Peskind Elaine R , Turner Robert W. , Wethe Jennifer , Rabinovici Gil D. , Johnson Keith A. , Tripodis Yorghos , Cummings Jeffrey , Shenton Martha E , Stern Robert A , Reiman Eric M. ,   for the DIAGNOSE CTE Research Project
Published: December 2022

AbstractBackgroundChronic traumatic encephalopathy (CTE) is a neurodegenerative disease that is characterized by perivascular foci of phosphorylated tau (p‐tau) notably in the depths of sulci, with varying patterns in the cerebral cortex. Prior studies show elevated flortaucipir (FTP) PET binding in former American professional football players(PRO). However, the association of p‐tau with clinical measures remains unclear using regional FTP SUVR as early signs of CTE related tau pathology. Graph theory (GT) takes advantages of the spatial variability in p‐tau load and allows the integration of regional measures to define GT based measures. Here we examine the GT based measures in two CTE cohorts to evaluate their utility in assessing p‐tau related pathology in CTE.MethodThe graph procedure was optimized in FTP PET images in a group of 26 PRO with reported cognitive and/or behavorial symptoms and 30 asymptomatic controls without a history of traumatic brain injury (the DETECT Study) and identified the GT measure, entorhinal tau strength, as the target metric with the best group separation between PRO and controls. The optimized graph procedures were then applied to the DIAGNOSE CTE Research Project dataset (99 former PRO, 51 former college football players [COL], and 52 controls without exposure to repetitive head impacts [CTL]) and we examined entorhinal tau strength’s ability to differentiate the exposure groups and relationship to consensus based diagnoses of Traumatic Encephalopathy Syndrome (TES), the clinical syndrome associated with CTE.ResultEntorhinal tau strength was significantly different among the three exposure groups (p=0.0001) similar to regional SUVR measures (Figure 1). Regional SUVR did not differentiate players (PRO+COL) with and without TES, while entorhinal tau strength approached although did not reach significance (Figure 2). Entorhinal tau strength is the only FTP measure that showed significant differences (p=0.006) between those players with cognitive impairment and players without (Figure 3).ConclusionWhile there is still considerable overlap in between‐group measurements, GT based entorhinal tau strength, is potentially more sensitive in detecting tau changes in players with and without TES. Additional studies are necessary to clarify the value of this new measure in detecting underlying CTE pathology.
Update on the TOGETHER study: a patient‐ and investigator‐blind, randomized, placebo‐controlled study evaluating the efficacy, safety and tolerability of bepranemab, UCB0107, in prodromal‐to‐mild Alzheimer’s disease
Authors: Barton Matthew E , Steen Bart Van Den , Van Tricht Hans L.G , Byrnes William , Purcell Fiona E , Southcott Sarah Ann , Raby Daniel , Starshinov Yaroslav Iurievich , Ewen Colin 
Published: December 2022

AbstractBackgroundBepranemab is a recombinant, humanized, full‐length IgG4 monoclonal antibody that binds to a central tau epitope (amino acids 235‐250). Here, we update on the progress of the TOGETHER study (AH0003; NCT04867616) with bepranemab in early Alzheimer’s disease (AD).MethodTOGETHER is a global, multicenter, double‐blind, placebo‐controlled, parallel‐group study investigating the efficacy, safety and tolerability of bepranemab versus placebo. Patients with prodromal (National Institute on Aging‐Alzheimer’s Association [NIA‐AA] Stage 3) or mild (NIA‐AA Stage 4) AD (target N = 450) will be randomized (1:1:1) to receive one of two doses of bepranemab or placebo (intravenous, every 4 weeks), over an 80‐week treatment period, followed by an optional 48‐week open‐label‐extension period. Participants will have a global Clinical Dementia Rating (CDR) score of 0.5 (prodromal AD) or 0.5–1.0 (mild AD) and a CDR‐Memory Box score ≥0.5 at screening and baseline, a score of ≤85 for the delayed recall domain of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), mini‐mental state examination (MMSE) ≥20 at screening and must meet the NIA‐AA 2018 definition of cerebral beta‐amyloid (Aβ) accumulation, by either a positive centrally read positron emission tomography (PET) scan or a positive cerebrospinal fluid (CSF) pTau181/Aβ1‐42 ratio. The primary endpoint is change from baseline to Week 80 in CDR scale Sum of Boxes total score. Secondary endpoints include: pharmacokinetics; safety and tolerability; tau PET imaging and change from baseline in AD Assessment Scale‐Cognitive Subscale 14, Amsterdam Instrumental Activities of Daily Living questionnaire and MMSE at Weeks 56 and 80.ResultAs of March 1, 2022, 56/125 planned centers have enrolled participants across 8 countries: Belgium, Canada, France, Netherlands, Poland, Spain, UK and USA. Of the 538 participants who entered screening, 62 have been randomized so far and 334 failed screening. Predominant reasons for screen failure include not meeting RBANS, MMSE or Aβ positivity (CSF or PET) criteria.ConclusionThis proof‐of‐concept study employs clinical outcome measures, imaging, pharmacokinetics, and biomarkers to assess the ability of bepranemab to slow progression of AD when administered in the early stages of disease. Enrollment and randomization are underway with nearly half of the study centers active.
Associations between Depression and Subjective Cognitive Decline: Results from the Study of Latinos‐Investigation of Neurocognitive Aging (SOL‐INCA) and HCHS/SOL
Authors: Guareña Lesley A. , Paredes Alejandra Morlett , Tarraf Wassim , Kuwayama Sayaka , Zlatar Zvinka , Stickel Ariana M , Gonzalez‐Pardo Roberto , Perreira Krista M , Wassertheil‐Smoller Sylvia , Zeng Donglin , Gallo Linda C , Daviglus Martha L , Isasi Carmen R , González Hector M 
Published: December 2022

AbstractBackgroundMany aging Hispanic/Latino persons are worried about memory loss. Prior research suggests that subjective cognitive decline (SCD) and depression, might have common pathways, and could be precursors to cognitive impairment. We examined associations between depression and domains of SCD in a large sample of diverse Hispanics/Latinos.MethodsData included n = 6,189 (unweighted) middle‐aged and older Hispanics/Latinos (Age M = 63.4‐years, SD = 8.2; 55% female; 40.5% with more than High School education) from 6‐heritage groups participating in the Study of Latinos‐Investigation of Neurocognitive Aging (SOL‐INCA), an ancillary study of the Hispanic Community Health Study/Study of Latinos (HCHS/SOL). We used survey generalized linear regression to model the associations between depressive symptoms, captured at baseline (2008‐2011) with the Center for Epidemiological Studies‐Depression 10‐Item Scale (CES‐D‐10), and SCD was measured, on average 7‐years later, via the Everyday Cognition Short‐Form (ECog‐12).ResultsHigher depressive symptoms at baseline were linked to worse global (B = .37, SE = .02) and domain specific SCD [Memory (B = .34, SE = .02), Visual Spatial Planning (B = .28, SE = .02), Executive (B = .33, SE = .02)] (ps<0.001) after adjusting for cardiovascular risk and demographic covariates. These associations were more pronounced in individuals who were concerned about their attention, concentration or memory. Hispanic/Latino background (i.e., Dominican, Central American, Cuban, Mexican, Puerto‐Rican, South American, Other) did not modify the associations between depression symptoms and measures of SCD (ps>0.05).ConclusionElevated depressive symptoms were consistently linked to global and domain specific subjective cognitive decline across Hispanics/Latinos of diverse heritages, particularly in the presence of attention, concentration or memory concerns. Our findings underscore the importance of assessing depression when evaluating Hispanics/Latinos with cognitive complaints.
Exploring Combination Therapies in AD: Additive Effects of the QPCT Inhibitor Varoglutamstat and Aducanumab on Aβ Pathology and Biomarkers In Vivo
Authors: Hoffmann Torsten , Schenk Mathias , Gnoth Kathrin , Ilse Victoria , Brunner Daniela , Rahfeld Jens‐Ulrich , Schilling Stephan , Schaeffer Michael 
Published: December 2022

AbstractBackgroundPyroglutamate‐3Aβ (N3pE), a toxic Aβ variant formed by the activity of glutaminyl gyclase (QPCT) has been shown to play a pivotal role in the development and progression of Alzheimer’s disease (AD). Recently, we demonstrated that a combination of the QPCT inhibitor varoglutamstat (PQ912) with the N3pE‐specific antibody m6 has an additive effect on lowering of N3pE in vivo. Here, we analyzed whether a similar additive effect could be achieved when combining varoglutamstat with the Aβ‐aggregate‐specific antibody aducanumab.MethodNine‐months old APPxhQC mice were treated with either varoglutamstat (1.6 g/kg chow, ad libitum), chimeric aducanumab (chAdu, ≈10 mg/kg i.p. weekly) or a combination of both for 16 weeks. Brain Aβ accumulation (ELISA and immunohistochemistry) and AD biomarkers in the water‐soluble brain fractions (neurogranin, BACE‐1, YKL‐40; ELISA) were analyzed and compared to a vehicle‐treated group.ResultTreatment with either varoglutamstat or chAdu significantly reduced the accumulation of both total Aβ and N3pE in the brain. The effect of chAdu was more pronounced for total Aβ (‐35% vs. ‐21% for varoglutamstat), while varoglutamstat treatment resulted in a stronger decrease of N3pE (‐28% vs. ‐19% for chAdu). The combination treatment generally led to a stronger decrease of Aβ vs. single agent treatment (Bliss combination index (CI) = 0.88 for soluble Aβ42 and 1.23 for insoluble Aβ42). For insoluble N3pE, the observed effect was nearly additive (CI = 1.09). Treatment with chAdu, varoglutamstat or both had different effects on the analyzed AD biomarkers. chAdu treatment significantly decreased BACE‐1 protein levels (‐30%), while varoglutamstat treatment significantly reduced levels of the brain inflammation marker YKL‐40 (‐27%), which is in line with earlier clinical Phase 2a study results.ConclusionOur data indicate that a combination of agents with different modes of action such as aducanumab, an Aβ aggregate‐specific antibody and varoglutamstat, a small molecule designed to block formation of toxic, aggregation‐prone N3pE, can act additively to decrease total Aβ and N3pE levels in the brain. Our results also provide a rationale for investigating different potential combination regimens, including an initial antibody‐mediated Aβ clearance followed by long‐term suppression of N3pE formation and inflammation by varoglutamstat (“treat and maintain”).
Cellular senescence profiling reveals distinct sub‐types of neurofibrillary tangle bearing neurons.
Authors: Orr Miranda E , Orr Timothy C , Dehkordi Shiva Kazempour , Zare Habil , Walker Jamie M. , Keene C Dirk 
Published: December 2022

AbstractBackgroundNeurons with tau‐containing neurofibrillary tangles (NFTs) closely correlate with Alzheimer’s disease (AD) progression and severity. Our prior work determined that NFT‐bearing neurons undergo a change in cell fate consistent with cellular senescence. The goal of this project was to determine whether senescent NFT‐bearing neurons differ from quiescent NFT‐bearing neurons.MethodPostmortem human AD brains were analyzed using GeoMx (NanoString, Inc) digital spatial profiling (DSP). Region of interest (ROI) selection included the presence or absence of neuronally expressed AT8 (phosphorylated tau, NFTs) and/or p19 (senescence). NFTs with or without p19 expression were compared to healthy neurons from the same cases. The expression of 86 proteins associated with neuropathology, inflammation, autophagy and cell typing was determined for each ROI and immediate environment (Fig. 1a‐b).ResultNFT‐bearing neurons with p19 (senescent) were significantly different than NFT‐bearing neurons without p19 (quiescent). Senescent NFT‐bearing neurons appeared similar to neurons without tau pathology. In contrast quiescent NFT‐bearing neurons displayed signs of crisis (i.e. apoptosis). Additionally, we revealed significant differences in tau phosphorylation at multiple epitopes between the two classes of NFT‐bearing neurons (Fig. 1c‐h).ConclusionThese data indicate the presence of distinct NFT‐bearing neuron subtypes in AD. Our ongoing studies are investigating (i) whether senescent or quiescent NFTs are more closely associated with pathogenesis, (ii) the transition between neuronal quiescence to senescence and (iii) which tau species contribute to this cell fate decision (self‐sacrificing versus disease propagating). More broadly, these results will provide a better understanding of distinct tau species in neurodegeneration which is critically important to clinical studies that are increasingly relying on tau biomarkers to predict disease onset, progression and target engagement in clinical trials.
A systematic review of locus coeruleus degeneration detected by neuromelanin sensitive MRI technique in patients with Alzheimer’s disease
Authors: Hou Ruihua , Chen Yuqing , Chen Teng 
Published: December 2022

AbstractBackgroundThe locus coeruleus(LC) is a bilateral nucleus located in the dorsal pontine tegmentum and is the major source of noradrenaline(NA), which plays a key role in cognition. While cognitive decline in Alzheimer disease(AD) has primarily been related to dysfunction within the cholinergic system in the nucleus basalis, there is considerable research evidence indicating extensive LC degeneration in AD, with some suggesting that it is among the earliest pathologies. Therefore, the early vulnerability of the LC to AD is of considerable clinical significance, as this raises the possibility that changes of the LC activity may provide early detection markers for diagnosis as well as early intervention targets to delay AD progression. However, the contribution of LC degeneration to cognitive decline in the development of AD has been underappreciated due to methodological difficulties, with most evidence coming from animal and post‐mortem studies. The absence of reliable non‐invasive direct measures of the LC remains the biggest challenge. Recent research indicates that LC visibility is driven by neuromelanin content of noradrenergic neurons and the intrinsic neuromelanin‐sensitive MRI technique enables direct visualisation of the LC.MethodsA systematic search of the literature was performed on electronic databases including PubMed, Web of Science, and Embase. Human imaging studies employing neuromelanin‐sensitive MRI technique to measure LC degeneration were included in this review. Screening, data extraction, and quality assessment were undertaken following PRISMA guidelines for preferred reporting of systematic reviews.ResultsLC‐contrast ratio or LC‐signal intensity detected by the neuromelanin‐sensitive MRI were found to be significantly reduced in patient groups with Alzheimer's disease compared with the healthy control group in all included studies, with recent evidence indicating its significant association with levels of CSF amyloid.ConclusionsThe current systematic review strongly supports the use of the neuromelanin‐sensitive MRI technique to detect the LC degeneration as a biomarker for AD neuropathology. Future research are warranted to characterize how LC signals evolve at different stages of AD, which could lead to novel intervention approaches to delay or prevent cognitive decline.
Treating Alzheimer’s Disease via Donepezil Hydrochloride Loaded Nanoparticles: A Novel Approach for Brain Drug Delivery
Authors: Garg Yogesh , Bhatia Amit 
Published: December 2022

AbstractBackgroundMany neuroprotective agents (like donepezil hydrochloride) have poor permeation to brain through blood brain barrier. Thus, there is a need to develop a new drug delivery system that can improvise the release of neuroprotective agents/drugs directly into brain avoiding blood brain barrier.MethodDonepezil hydrochloride loaded chitosan nanoparticles were developed by ionic gelation method and optimized using Design of Experiment (DoE) approach.ResultThe optimized formulation had shown mean particle size (177.8 nm), zeta potential (+ 16.6 mV), drug payload (22.2 mg/100 mg of chitosan), process yield (91.96%) and mucoadhesive strength (9.26 g). In‐vitro release and ex‐vivo diffusion of drug from nanoparticles were found be > 90% and >70% in 24 hours, respectively. The delivery of drug to rat brain was found to be three times higher with nanoparticles vis‐à‐vis its solution. Further, confocal laser scanning microscopy confirmed the grater extent of localization by nanoparticles in the brain after nasal administration.ConclusionFrom the above results, it was concluded that the nose to brain delivery of donepezil hydrochloride using mucoadhesive nanoparticles has better potential as compared to conventional formulation approach for brain drug delivery.
Longitudinal lipidomic analyses in patients undergoing therapeutic plasma exchange with albumin replacement as a treatment for Alzheimer’s disease
Authors: Minguet Carla , Ortiz Ana Maria , Gonzalo Ricardo , Horrillo Raquel , Núñez Laura , Ruiz Agustin , Lopez Oscar L. , Boada Mercè , Páez Antonio , Costa Montserrat 
Published: December 2022

AbstractBackgroundDifferences in ceramides, glycerides, phospholipids, cholesterol esters and fatty acids (FA) lipid subclasses have been reported between Alzheimer’s disease (AD) patients and healthy subjects (Liu et al. Transl Psychiatry 2021;11:344). The AMBAR phase 2b/3 trial is a therapeutic approach for mild‐moderate AD patients (MMSE:18‐26) based on a 14‐month program comprising 18 plasma exchange procedures with albumin replacement (PE‐Alb) to remove neurotoxic Aβ and other pathological substances from plasma, thus slowing AD progression (Boada et al. Alzheimers Dement 2020;16:1412). The aim of this study was to assess PE‐Alb effects on lipidomics across the AMBAR study.Method250 metabolomic biomarkers were quantified from serum samples of 309 individuals included in the AMBAR study using high‐throughput proton NMR (Nightingale Health Ltd, Helsinki, Finland). Up to 236 PE‐treated and 73 placebo [sham‐PE] patientsâ€™ samples, at 3 time points, were assessed. Raw metabolic levels were log2 normalized and scaled. Biomarkers were analyzed with a mixed model for repeated measures including fixed effects factors for month, treatment group and month*treatment group interaction, adjusted for baseline MMSE, age, sex, BMI, apoε4, lipid‐lowering medication, baseline biomarker levels and patient as a repeated factor. Differences from placebo as fold change (FC) were assessed through month*treatment group interaction term estimates.Result57 metabolomic biomarkers showed statistical significance (Adj.p‐value <0.05) of PE‐treated patients compared to placebo at the end of study (EOS, 14 months). All significant metabolites were up‐regulated in PE‐treated patients vs placebo. 45/57 significant metabolites belonged to lipidomic subclasses such as cholesterols (including cholesteryl esters), glycerophospholipids and fatty acids. Polyunsaturated FA (docosahexaenoic acid and linoleic acid), which may have a positive role against AD (Heath et al. Int J Mol Sci 2021;22:11826), were significantly increased at EOS (Adj.p‐value 0.038 and 0.020; linear‐FC=1.2 both), while saturated and monounsaturated FA were not (Adj.p‐value 0.19 and 0.735, respectively). Similarly, phosphatidylcholine levels, reported as altered in AD (Whiley et al. Neurobiol Aging 2014;35:271), were significantly upregulated (Adj.p‐value 0.049, linear‐FC=1.2) at EOS.ConclusionPE‐Alb procedures used in AMBAR induced changes in lipidomic profiles. This supports the multimechanism basis of AMBAR therapeutic approach that may contribute to slowing AD progression.