bluuebunny/crossref_metadata_2025_split huggingface dataset:
Are changes in muscular strength following head‐down bed rest independently associated with improved cognitive function in older adults? A secondary analysis of a randomized controlled trial
Authors: Zou Jammy , Falck Ryan S , Balbim Guilherme Moraes , Davis Jennifer C , Madden Kenneth , Handy Todd C , Liu‐Ambrose Teresa 
Published: December 2023

AbstractBackgroundPhysical inactivity is common among older adults and is a risk factor for cognitive decline. Even a brief period of physical inactivity, such as bed rest due to hospitalization, in older adults has significant negative impacts. Exercise is strategy to counter the negative effects of physical inactivity. Exercise‐induced improvements in cardiorespiratory fitness is associated with improved cognitive function. Less is known regarding the contribution of exercise‐induced changes in muscle strength to changes in cognitive function. Thus, we aimed to examine the independent contribution of: 1) change in cardiorespiratory fitness; and 2) change in peak muscle torque of the lower extremity to changes in cognitive function in a randomized controlled trial (RCT) of head‐down bed rest (HDBR) vs. HDBR with exercise in healthy older adults.MethodAn analysis of a non‐blinded, parallel‐group, RCT of 22 healthy older adults (11 males and 11 females) aged 55‐65 years. Participants were randomized to: 1) 14 days of 6° HDBR (CON); or 2) HDBR with daily resistance and aerobic exercise training (EX). Outcome measures were taken at baseline and HDBR completion. The Flanker Inhibitory Control and Attention Task measured executive function. Physical fitness measures included: 1) maximal aerobic capacity (VO2max) using a bicycle ergometry test; and 2) knee extension isokinetic muscular strength (KE) using a Biodex dynamometer. We performed two separate multiple linear regressions to determine whether following 14 days of HDBR: 1) VO2max was associated with Flanker score, after accounting for ΔKE; and 2) KE was associated with Flanker score, after accounting for ΔVO2max. Each model was also adjusted for baseline Flanker score and the baseline physical fitness measure of interest.ResultAt baseline, average Flanker t‐score was 48.33, mean VO2max was 32.527 ml/kg/min, and knee extension strength was 64.472 Nm. VO2max at follow‐up was not significantly associated with Flanker performance (b = 0.232 ± 0.716; p = 0.635; R2
adj. = 0.285). However, greater KE strength was significantly associated with better Flanker performance (b = 2.023 ± 0.389; p = 0.043; R2
adj. = 0.633) at HDBR completion.ConclusionThe maintenance of muscle strength even during brief periods of physical inactivity appears to be critical for cognitive health in older adults.
Real‐time Memory‐related Neurofeedback Training Improves Intrinsic Brain Oscillations in Older Adults
Authors: Liu Ziming , Jiang Yang , Cerel‐Suhl Sylvia , Suhl Jeremiah , Zhao Xiaopeng 
Published: December 2023

AbstractBackgroundMild cognitive impairment (MCI), manifesting as working memory deficits for example, is the most common and earliest symptom of Alzheimer’s disease and related dementias (AD/ADRD). To combat the brain aging processes, early intervention is needed. Electroencephalogram (EEG)‐based neurofeedback (NF) has been found to be beneficial in treating a variety of brain disorders. Increased intrinsic delta power and decreased alpha is associated with brain aging and AD pathologies. We have developed an ERP‐based NF protocol to reward memory‐related potentials. In this study, we aim to evaluate the effect of NF training protocol.MethodThree older males (ages, 63, 78, and 79) participated in a newly developed NF training protocol including baseline and memory‐related NF training (twice a week). Each participant was recorded using 90‐second of eyes closed (EC) before multiple NF sessions during each visit. Their brain signals were collected with a 14‐channel wireless electroencephalogram (EEG) headset and processed in real‐time. The NF training contained 2 sham sessions followed by 2 intervention sessions. Compared to the intervention, visual feedback in the sham was provided in random order rather than triggered by participants’ ERP fluctuations. The EEG signal collected with EC before the experiment (Baseline, T0), 3 days after the sham (Sham, T1), and 3 days after the intervention (post‐intervention, T2) were preprocessed as 4s epoch windows and computed as the delta, theta, alpha, beta, and gamma band power. The average EEG band powers from T0, T1, and T2 and memory performances from the three participants were calculated.ResultThe working memory performance (accuracy and reaction times during retrievals of memory target and rejection of nontarget) did not show significant change among the three participants. In contrast, the EC intrinsic delta and alpha power changed towards brainwaves seen in younger brains after several sessions of NF training. Additionally, sham also improves in the alpha band (associated with attention and vigilance).ConclusionThe pilot results demonstrated the effectiveness of a newly developed NF training using working memory related potentials in two out of three older adults. The results indicate the promise of cognitive enhancement using event‐related potentials‐based NF training in real time.
Genomic analysis of fibroblasts from marmosets carrying early‐onset Alzheimer’s disease mutations in PSEN1
Authors: Carter Gregory W , Haber Annat , Duong Duc M. , Seyfried Nicholas T , Murai Takeshi , Schultz Laura , Huhe Hasi , Choi Sang‐Ho , Kofler Julia , Schaeffer David J , Hachem Stephanie , Mou Yongshan , Ha Seung‐Kwon , Park Jung Eun , Homanics Gregg E , Strick Peter L , Rizzo Stacey J Sukoff , Silva Afonso C 
Published: December 2023

AbstractBackgroundAlzheimer’s disease (AD) is the most prevalent form of dementia and remains generally untreatable. The slow, age‐related development of AD and inaccessibility of early‐stage brain tissue has limited our understanding of its origins and progression. Large‐scale genetic studies and molecular analysis of postmortem brain samples have nominated dozens of candidate genes and proteins for therapeutic targeting or diagnostic biomarkers, generating a need for in vivo systems to study the underlying biological dysfunction and perform preclinical testing. Here, we report on genetic, genomics, and proteomic analysis of fibroblast lines derived from a colony of marmosets genetically engineered with rare familial variants in the PSEN1 gene.MethodWe performed whole‐genome sequencing on 14 individuals, including six mutant carriers. We validated the presence of the PSEN1 mutations and assessed variation at multiple other Alzheimer’s disease loci. Fibroblast cultures were obtained from 12 animals and assayed using a Nanostring AD gene expression panel and label‐free proteomics. This allowed us to quantify 800 transcripts and 2165 proteins per sample.ResultWe detected differential gene expression for genes enriched in neuron development and amyloid‐beta regulation, providing strong evidence for the functional relevance of the engineered variants. We quantitatively compared changes in marmoset PSEN1 fibroblasts to similar molecular measures in postmortem brain tissue and induced pluripotent stem cells (iPSCs) from human AD studies. Both gene and protein expression changes in the undifferentiated fibroblasts correlated with changes in iPSCs from human AD carriers reprogrammed into neuronal lineages. We also observed both transcriptomic and proteomic changes in marmoset PSEN1 cells that match those in postmortem AD brains.ConclusionThese findings demonstrate that disease‐relevant pathways and processes are altered in fibroblasts from mutant marmosets, provide a roadmap for more advanced molecular studies of AD in aging marmosets and marmoset‐derived cell models, and outline a strategy to align marmoset models with human disease to facilitate robust translation.
Plasma phosphorylated tau 217 levels are highly stable under common pre‐analytical sample handling procedures
Authors: Gouda Mariam , Antwi‐Berko Daniel , van Leeuwenstijn Mardou S. S. A. , Hussainali Zulaiga , Bongers Bram , Vanbrabant Jeroen , in ’t Veld Sjors G.J.G. , Edelmayer Rebecca M. , Stoops Erik , Jeromin Andreas , Teunissen Charlotte E. , Verberk Inge M.W. 
Published: December 2023

AbstractBackgroundThe Standardization of Alzheimer’s Blood Biomarkers working group issued a standardized operating procedure (SOP) to mitigate effects of common pre‐analytical sample handling procedures on the Alzheimer’s blood‐based biomarkers. This SOP was based mainly on results obtained with blood‐based amyloid‐beta40 and amyloid‐beta42 assays. Now that various blood‐based phosphorylated (p)Tau assays enter the fore, we need to re‐assess the validity of the proposed blood handling SOP. We aimed to understand the effect of common pre‐analytical sample handling procedures on blood pTau217 levels.MethodBlood was obtained from 62 volunteers at the polyclinic phlebotomy department (n = 31) and the Alzheimer Center Amsterdam (n = 31) of Amsterdam University Medical Centers. Blood samples from volunteers were handled according to one of the following experiments: variation in primary collection tube (K2EDTA versus serum, sodium‐citrate, lithium‐heparin), delayed centrifugation of K2EDTA tubes while kept at room temperature (RT; 20‐25°C) or in the fridge (2‐8°C; 30min versus 4h, 7h, 24h, 72h), hemolysis of K2EDTA plasma (no hemolysis versus low (100mg/dL hemoglobin) and high (500 mg/dL hemoglobin)) and repeated freeze‐thawing (FT) of K2EDTA plasma (no additional FT versus +1, +2, +4FT). Sample sets were measured with the pTau217 AlzPath prototype assay on the Simoa HD‐X. Recovery% was calculated as the concentration measured in the experimental condition divided over the concentration measured in the relevant reference condition. Median recovery change >10% was considered relevant.ResultEffects of the pre‐analytical sample handling variations on plasma pTau217 levels are presented in figure 1. Blood‐based pTau217 levels were highest in K2EDTA plasma (median (interquartile range (IQR)) %Recovery compared to K2EDTA, in serum: 34% (29‐42%), in sodium‐citrate: 21% (15‐27%), in lithium‐heparin: 7% (6‐8%)). Delayed centrifugation up to 72h either when tubes were kept at RT or when kept cold did not affect pTau217 levels, neither did hemolysis and repeated freeze‐thawing.ConclusionUsing a primary collection tube other than K2EDTA results in substantially lower pTau217 levels. Otherwise, pTau217 level seems highly stable in plasma under diverse pre‐analytical sample handling conditions. According to the results, the consensus pre‐analytical blood handling SOP as published by the Standardization of Alzheimer’s Blood Biomarkers working group is still valid.
Inflammation blood profiles across neurodegenerative diseases
Authors: Malpetti Maura , Swann Peter , Chouliaras Leonidas , Ashton Nicholas J. , Tsvetanov Kamen A , Street Duncan , Whiteside David J , Cope Thomas E , Savulich George , Rittman Timothy , Surendranathan Ajenthan , Murley Alexander G , Stockton Katherine , Bevan‐Jones W Richard , Prats‐Sedano Maria A , Su Li , O'Brien John T , Rowe James B. 
Published: December 2023

AbstractBackgroundBrain inflammation is an important pathogenic mechanism in many dementias, occurring early in the disease and being predictive of clinical decline. However, data on blood markers of inflammation across different dementia subtypes are limited. Here we assess inflammatory patterns of serum cytokines from patients with Alzheimer’s disease (AD), Lewy‐body dementia (DLB), frontotemporal dementia (FTD), progressive supranuclear palsy (PSP), corticobasal syndrome (CBS) and motor neurone disease (MND).MethodBlood samples were obtained from 422 participants (29 controls, 46 patients with AD, 35 with mild cognitive impairment (MCI), 38 with DLB, 52 with behavioural variant FTD, 51 with primary progressive aphasia, 58 with PSP, 53 with CBS, 60 with MND. Serum assays for 41 inflammatory markers used the MesoScale Discovery V‐Plex‐Human Cytokine 36 plex panel plus five additional cytokine assays. A Principal Component Analysis (PCA) across all participants was used to identify leading multivariate components, or profiles, of inflammation. Analysis of variance and Bayesian pairwise t‐tests were performed on the resulting components to compare each patient cohort to controls.ResultFifteen cytokines were undetectable in the majority (>50%) of participants and were thus excluded. The PCA of remaining 26 cytokines identified 3 components (explaining 18.3%, 8.5% and 6.4% variance, respectively). Component 1 was strongly represented by pro‐inflammatory cytokines (Figure 1, left). Kruskal–Wallis one‐way analyses of variance on the first component detected significant differences across the groups (χ2(8) = 24.3, p = 0.0021), and the Bayesian pairwise t‐tests identified significant differences between each patient cohort and controls, except for people with MCI (Figure 1, right). Component 2 did not differ between patients and controls. Component 3 split the cytokines into two subgroups, and was mainly loaded by patients with MCI, AD and MND (χ2(8) = 64.6, p<0.0001).ConclusionThis data‐driven approach identified similar profiles of pro‐inflammatory responses across multiple neurodegenerative dementia types. Further analyses will clarify differences between diagnoses, relationships of the pro‐inflammatory patterns with clinical severity and brain changes captured by neuroimaging (PET and MRI).
Biomarkers disclose associations between Neuroinflammation and Synaptic Depletion in AD.
Authors: Rahmouni Nesrine , Woo Marcel , Tissot Cécile , Servaes Stijn , Therriault Joseph , Stevenson Jenna , Benedet Andrea Lessa , Ashton Nicholas J. , Zetterberg Henrik , Blennow Kaj , Pascoal Tharick Ali , Zimmer Eduardo R , Rosa‐Neto Pedro 
Published: December 2023

AbstractBackgroundWhile in healthy conditions, synaptic function is sustained by the interplay between neurons and glial cells. The presence of Alzheimer’s disease (AD) pathophysiology might impose synaptic alterations via neuroinflammatory responses from microglia and astrocytes. Imaging and fluid biomarkers allow for testing this conceptual framework in living individuals. Here, we aim at uncovering the associations between neuroinflammatory and synaptic markers in aging and AD.MethodParticipants were recruited from the Translational Biomarker for aging and dementia cohort (TRIAD). We analyzed cognitively unimpaired young (CUY, N = 20), cognitively unimpaired older adults (CU; N = 48) individuals, patients with mild cognitive impairment (MCI; N = 24), AD dementia patients (ADD; N = 16) participants. The endpoints were CSF 14‐3‐3 sigma‐delta (ζδ), CSF Growth Associated Protein 43 (GAP43) and neurogranin as markers of synaptic dysfunction. We modeled associations between these synaptic biomarkers with astrocyte and microglial related inflammatory markers as well as tau, amyloid and neurodegeneration biomarkers.ResultAccording to ROC analyses contrasting CSF biomarkers, 14‐3‐3 ζδ was able to discriminate amyloid‐ β pathology in cognitively impaired individuals (AUC = 0.88) (Figure 1). The amyloid‐induced 14‐3‐3 ζδ increase was mediated by inflammatory astrogliosis measured by GFAP, whereas the tau induced 14‐3‐3 ζδ pathology was mediated by anti‐inflammatory cytokines (Figure 2). CSF levels of GAP43 and neurogranin were positively associated with TSPO measured with [11C]PBR28(Figure 3.1) and GFAP (Figure 3.2). [11C]PBR28 cluster‐based SUVRs was positively correlated to concentrations of (A) Neurogranin (p = 5.8e‐08) and (B) GAP‐43(p = 6.8e‐10).ConclusionThe present observations support the framework in which glia‐related neuroinflammatory responses contribute to synaptic alterations in carriers of AD pathophysiology. We will discuss the implications and limitations of this framework.
18F GTP1 Tau PET image‐derived features improve the prediction of CDR‐SB progression in a multi‐modal model in prodromal to moderate AD
Authors: Toth Balazs , Bohorquez Sandra Sanabria , Monteiro Cecilia , Clayton David , Hibar Derrek P. , Anania Veronica , Abramzon Daniel , Sink Kaycee M. , Bittner Tobias , Teng Edmond 
Published: December 2023

AbstractBackgroundPrevious work from our group has shown that a model using a limited number of common clinical, demographic and MRI features can robustly predict CDR‐SB progression (Hibar et al. CTAD 2021) and that baseline Tau‐PET levels are associated with subsequent cognitive decline (Teng et al., 2021). However, the gain from combining these predictors has not previously been assessed. The aim of this work was to assess the additive prognostic value of including baseline [18F]GTP1 tau‐PET with the other common predictors.MethodBaseline [18F]GTP1 images and MRI features were available from two crenezumab (NCT02670083 and NCT03114657; n = 51) and two semorinemab (NCT03289143; n = 360 and NCT038287747 placebo arm; n = 113) randomized clinical trials in prodromal to moderate AD populations. The benchmark linear model included age, sex, APOE4 status, education, diagnosis, baseline ADAS‐Cog 11, ADCS‐ADL, CDR‐SB and MMSE and hippocampus, ventricles and whole brain volume as predictors. In addition, the extended model included the whole cortical grey and temporal meta‐ROI [18F]GTP1 SUVR. A gradient boosted decision tree ensemble (XGBoost) model aimed to uncover potential nonlinearities and interaction among the features. Model performance was evaluated by r2 using bootstrapped confidence intervals and calibration.ResultOur analyses included data from 524 participants (prodromal AD: 151, mild AD: 318, moderate AD: 55). The benchmark model yielded r2 = 0.175 [CI 0.122 – 0.241] with CDR‐SB in the overall sample. The [18F]GTP1 only model had r2 = 0.122 [0.071 – 0.185]. The extended linear model yielded r2 = 0.226 [0.163 – 0.299] and remained well calibrated. Point estimates of r2 were lower in the prodromal and mild versus the moderate subgroups. The performance of the XGBoost model on the holdout set (r2 = 0.230 [0.123 – 0.382]) was marginally better than the linear model, but results were variable among the diagnosis subgroups and further validation needs to be performed on a larger independent dataset.ConclusionThe extended model including [18F]GTP1 SUVR features showed increased performance relative to the benchmark model. Therefore, [18F]GTP1 SUVR features may provide additional, meaningful information about patient prognosis and may be used as covariate adjustment factors to enhance treatment efficacy estimates in clinical trials. Analysis using [18F]GTP1 SUVR in other brain regions is being evaluated.
Late life learning, dementia, and overall health in underresourced settings: an investigation of the University for Seniors in Beirut, Lebanon
Authors: Elbejjani Martine , Hazzouri Adina Zeki Al , Kezios Katrina L , Sibai Abla 
Published: December 2023

AbstractBackgroundIdentifying modifiable factors that reduce Alzheimer’s disease and related dementias (ADRD) risk is a global public health priority. Several key social determinants of ADRD, such as years of education, are completed earlier in life, and thus are unamenable to change in older age. Evidence on the protective benefits of engaging in cognitively stimulating activities suggests that late life learning (“LLL”, non‐formal educational activities outside formal credentialed learning) may provide a unique window of opportunity, in older age, to mitigate ADRD risk by providing prospects for intellectual stimulation and social engagement. Yet, studies assessing assessed the benefits of LLL are scarce. Evaluations of cognitive and social benefits for LLL are particularly relevant for low‐resourced settings, where opportunities for engaged aging are limited.MethodWe designed a prospective cohort study (the LLL and Cognition 3LC study), capitalizing on an established and ongoing LLL program at the American University of Beirut, The
U
niversity
f
or
S
eniors (UfS). The UfS has been running for over 11 years, allowing to assess shorter‐ and longer‐term LLL influences on cognitive and overall health. Living in Lebanon, our population of older adults have endured multiple lifecourse and recent adverse psychosocial exposures. Our project will also examine the role of LLL in older age in mitigating the impacts of earlier psychosocial adversities on health.ResultOur project is embedded within a capacity building program and close collaborations between researchers in the US and Lebanon, providing an infrastructure for research on dementia and psychosocial disparities in Lebanon and the region. We aim to recruit 500 previously enrolled UfS participants, 200 newly/prospectively enrolled UfS participants, and 700 age‐ and sex‐matched non‐UfS‐participating community residents (Figure 1). We plan to conduct cognitive assessments at baseline and a follow‐up visit using cognitive batteries designed aligned with the Harmonized Cognitive Assessment Protocol (HCAP). For a formal program evaluation of LLL on cognition and related outcomes, we will implement advanced analytical techniques (e.g., difference‐in‐difference estimation) (Figure 2).ConclusionOur project aims to build a longitudinal cohort study, together with research and infrastructure capacities, to delineate LLL opportunities for dementia prevention in Lebanon and neighboring countries.
The Medical and Cognitive Research Unit in Austin Health, Australia
Authors: Woodward Michael 
Published: December 2023

AbstractThe Medical and Cognitive Research Unit (MRCU), Austin Health and University of Melbourne, is sited in Heidelberg, Australia at Austin Health, a large University Teaching Hospital. Part of the Aged and Continuing Care Department, it is headed by geriatrician Associate Professor Michael Woodward.MCRU employs 25 staff‐ nurse coordinators, psychologists, medical doctors, scientists and administrative. Some 10 research affiliates each year complete projects in collaboration with the department, but the main focus is sponsored clinical trials. Research areas include Investigational Products for AD, with over 200 Phase 1‐4 trials completed over the last 30 years. Other research foci include wound healing, immunization and frailty.AD research is accelerated when the skills to recruit into and conduct trials are developed and maintained in this centre of excellence. Close affiliation with clinical cognitive practice, including the Austin Health Memory Clinic and private practices of doctors working in MCRU attracts patients to such services, providing a pipeline of patients suitable for studies. These patients also contribute to large data bases, including the Alzheimer’s Disease Network (ADNet) and the Australian Imaging, Biomarkers and Lifestyle study (AIBL), and inturn these studies identify patients suitable for clinical trials in MCRU. The Head is one of 3 Medical Advisors to Dementia Australia, and as a member of the Dementia Australia Research Foundation funds dementia research throughout Australia. Numerous media exposures involve MCRU staff, raising national awareness of AD and related disorders‐ eg a recent National TV Documentary on mAbs for AD.International AD research looks to large sites to conduct trials, and inturn these site develop research protocols and contribute to national and international meetings. MCRU has recently contributed to protocols involving several small molecules to treat AD.International collaboration is a hallmark of a successful AD Research Centre‐ MCRU through AIBL and ADNet, and the affiliated Florey, have collaborated with ADNI and the World Wide FINGERS initiatives to better understand and prevent AD and related disorders.