bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mid‐life obesity and metabolic dysfunction in a genetically diverse mouse model of Alzheimer’s disease
Authors: Dunn Amy R. , Hadad Niran , Kaczorowski Catherine C. , O'Connell Kristen M.S. 
Published: December 2020

AbstractBackgroundAge and genetic background are the greatest risk factors for Alzheimer’s disease, but obesity and metabolic syndrome increase the risk of developing AD, as increased BMI at mid‐life is associated with an earlier age at onset for AD dementia. Furthermore, many AD patients also present with non‐cognitive symptoms associated with metabolic dysfunction, such as weight loss, changes in appetite, and low circulating leptin levels, which often occur prior to the onset of cognitive decline. Thus, systemic metabolic function may be an important, causal factor in the etiology of AD in humans. However, the mechanisms underlying this dysfunction and its relationship to disease onset, progression, and severity are poorly understood.MethodsWe assessed metabolic function in mice from our recently developed model of human AD, the AD‐BXD genetic reference panel (Neuner, et al 2019). Metabolic function was measured in 39 AD‐ and non‐transgenic (Ntg) strains using indirect calorimetry in Promethion metabolic cages to measure energy expenditure, VO2and VCO2, respiratory exchange rate (RER), locomotor activity, food and water intake, and sleep. To model mid‐life obesity, a subset of age‐ and sex‐matched AD‐ and Ntg‐BXD mice were fed a high‐fat/high‐sugar diet (HFD) starting at ∼2.5 months of age.ResultsAD‐BXD mice weigh less than their non‐transgenic counterparts; assessment of body composition indicates this is due primarily to a loss of fat mass. AD‐BXD strains also exhibited an increase in rearing behavior, which may indicate hypervigilance. Female AD‐BXD strains exhibited increased energy expenditure and locomotor activity and failed to develop diet‐induced obesity when fed HFD. Mice fed HFD generally displayed changes in RER consistent with a shift to fat metabolism; we further observed changes in patterns of food intake.ConclusionsOur data indicate that AD‐BXD mice exhibit some degree of metabolic dysfunction and that this is exacerbated by HFD. Analyses indicate that metabolic dysfunction at cognitively presymptomatic ages is correlated with memory deficits later in life. Ongoing work will quantify the impact of genetic background on these traits and relationships between metabolic and cognitive phenotypes.
Interrogating the role of the noradrenergic locus coeruleus in memory encoding in aging
Authors: Ludwig Mareike , Hammerer Dorothea , Lüsebrink Falk , Düzel Emrah 
Published: December 2020

AbstractBackgroundThe locus coeruleus‐norepinephrine system (LC‐NE system) supports the process of encoding of emotionally salient events. LC integrity varies in healthy elderly and is associated with altered cognitive functions in aging. Post‐mortem as well as structural indicators suggest that the modulation of the LC‐NE system is reduced in elderly. This reduction in ageing is also of note as it might be one of the earliest pre‐symptomatic indicators of dementia‐related brain pathology. Indeed, LC neuron degeneration is already observable in early stages of tau pathology before any cognitive symptoms are clinically notable in Alzheimer´s disease (AD). The main aim of this study was to investigate age differences in functional activations of the LC during (emotionally) salient events.MethodA total of 50 people (28 younger, 22 older healthy adults) participated in the experiment. A reversal learning task has been chosen as it provokes the release of NE. The study used neuromelanin (NM) ‐ sensitive magnetic resonance imaging (MRI) and high‐resolution functional MRI (fMRI) to visualise age differences in LC structure and function. Functional indicators can add sensitivity over structural indicators, which is important considering the fact of neuronal function loss before cell death occurs.ResultReduced LC integrity was related to lower memory performance for negative emotional events in elderly only. Moreover, unexpectedly, stronger functional responses of dopaminergic and noradrenergic midbrain structures to (emotionally) salient events during memory encoding were observed in older adults.ConclusionThese results are discussed in light of age differences in adapting to high and low levels of task difficulty. The study has shown the feasibility of investigating age differences in neuromodulatory nuclei. Therefore, the observed reduction in LC integrity might be a typical sign of healthy ageing or a sign of mild cognitive impairment (MCI) and thus also for AD.
Fibronectin accumulation and oxidative modification in Alzheimer’s disease
Authors: Farr N. Drew , Kraner Susan D. , Nelson Peter T. , Norris Christopher M. , Sompol Pradoldej 
Published: December 2020

AbstractBackgroundOxidative stress in Alzheimer’s disease (AD) alters the structure of brain proteins, complicating the pathophysiology of AD while suggesting potential drug targets. Fibronectin mediates cell attachment and function, in part by directing the reorganization of the extracellular matrix. High molecular forms of fibronectin appear more frequently and in higher amounts in AD while oxidative stress can cause nitration of fibronectin by 3‐nitrotyrosine. Considering the role of fibronectin in maintaining vessel function, accumulation/oxidative modification of fibronectin may alter vessel function. Astrocytes are also damaged in AD, with significant physiologic consequences. In healthy brain, astrocytes maintain the integrity of the neurovascular unit by maintaining molecular, metabolic, and cellular homeostasis. In AD, phenotypically distinct astrocytes may play a role in neurovascular function. Combined with compromised astrocyte function, oxidative modification of fibronectin may further damage AD brains that are already less capable of repair.MethodAstrocytic fibronectin and β‐amyloid were quantified in WT and 5xFAD mice (n = 6‐8 mice/group) using confocal microscopy and Western blot. GFAP, fibronectin, nitrotyrosine, and β‐amyloid were also immunolabeled in postmortem human AD and age‐matched control tissue and imaged using confocal microscopy.ResultWe showed that fibronectin was increased in hippocampal astrocytes in 5xFAD vs. WT mice (p = 0.032). In 5xFAD brain homogenates, fibronectin was increased by 30% compared to WT. In human tissue, both fibronectin and nitrotyrosine were increased compared to control. Fibronectin also accumulated around β‐amyloid plaques while fibronectin and nitrotyrosine colocalized in perivascular astrocytes, suggesting oxidative modification of fibronectin in human AD compared to control. We also observed morphologic changes in human AD astrocytes. AD white mater showed more fibronectin and nitrotyrosine in astrocytes compared to gray matter as well as more fibronectin in the extracellular space. Fibronectin was especially concentrated in the perivascular white matter.ConclusionOxidative changes to fibronectin in AD clustered in perivascular astrocytes, suggesting the central role of astrocytes in AD‐related vascular dysfunction.
Examination of a composite walking measure to inform physical activity guidelines for improving or maintaining cognitive functioning
Authors: Desai Pankaja , Halloway Shannon , Dhana Klodian , Holland Thomas Monroe , de Leon Carlos Mendes , Evans Denis A , Morris Martha Clare 
Published: December 2020

AbstractBackgroundFewer than half of all U.S. adults achieve recommended levels of aerobic activity (150 minutes or more at moderate intensity) (CDC, 2013; USDHHS, 2018). Information related to frequency, dose, duration, and intensity of walking needed to positively impact cognitive function in older adults remains unclear in current U.S. Physical Activity Guidelines (Piercey et al., 2018; Paterson et al., 2010). A paucity of studies have been conducted which examine the association between physical activity (PA), much less PA types, and cognitive function, using a longitudinal, population‐based approach with a racially diverse sample, which limits generalizability of existing findings. Self‐report PA measures often evaluate types of walking separately (e.g., walking for exercise, leisure time, occupational, transportation‐related), without considering total effect of all types of walking on cognitive function. A composite walking measure could provide a more comprehensive picture of perceived daily walking. We examine the association between composite walking and cognitive function and perceptual speed among participants in the Chicago Health and Aging Project (CHAP) over time.MethodCHAP is a longitudinal, population‐based study, which examined risk factors of Alzheimer’s Disease and chronic conditions among diverse older adults (Bienas et al., 2003). Data collection included self‐report walking frequency and duration, demographics, chronic conditions, cognitive activities, APOE ϵ4, and cognitive function during three‐year cycles. A composite walking measure was developed. Composite walking was divided into three categories determined by sample size: no walking, < 105 minutes/ week, and >105 minutes/ week of walking. Mixed effects regression analyses were conducted to test the association between walking and cognitive function and perceptual speed.ResultThe sample consists of N=4,320 CHAP participants (Black/ African American: 65%; Female: 65%; Mean Education: 13 years; Mean Age: 75 years). Findings show that composite walking had a statistically significant association with global cognitive function (category 2 β=.0084, p=.0389; category 3 β=.0099, p=.0187) and perceptual speed (category 2 β=.0117, p=.0164; category 3 β=.0162, p=.0013), after controlling for covariates.ConclusionAlthough it is best to follow PA guidelines, walking for lesser than the recommended amount may still be beneficial for cognitive function, which is useful for promotion of PA among sedentary older adults.
Alzheimer’s disease variant portal (ADVP): Harmonized genetics data and evidence collection for Alzheimer’s disease
Authors: Leung Yuk Yee , Kuksa Pavel , Qu Liming , Zhao Yi , Katanic Zivadin , Kuzma Amanda B. , Fu Wei , Liu Chia‐Lun , Tzeng Kai‐Teh , Valladares Otto , Chou Shin‐Yi , Naj Adam C. , Schellenberg Gerard D. , Wang Li‐San 
Published: December 2020

AbstractBackgroundAlzheimer’s disease (AD) genetic findings span progressively large genome‐wide association studies (GWASs) and meta‐analyses, with no single resource providing unified, searchable information on identified genetic variants and genes and supporting functional genomic evidence. We developed ADVP (Alzheimer’s Disease Variant Portal), a curated and harmonized interactive platform that provides unified access and visualization of a uniquely extensive up‐to‐date collection of GWAS data for AD.MethodsThe contents of ADVP database are curated from high quality genome‐wide significant loci reported in literature. We included all AD GWAS publications by Alzheimer’s Disease Genetics Consortium (ADGC) over the last ten years as a starting point and all other AD studies in GWAS catalog/GWAS central (MeSH D000544). For each publication, we systematically recorded all the association results reported in the main text. To facilitate curation, we developed a minimal set of information (meta‐data schema) to ensure all findings are annotated with the same information, including publication, association (variant rsID, genomic position, gene, association test results (p‐value, beta, odds ratio), effect allele, etc), phenotype, study design, target population, GWAS characteristics (size, number of cases/controls) among others. Collected data were organized into publication, variant, association, and evidence (functional genomics) database tables.ResultsADVP web interface provides multiple views of underlying data allowing browsing individual variants, genes, studies, genomic regions, genome‐wide/chromosome variant maps (interactive ideograms), and genome browser views incorporating functional genomics data. ADVP is also integrated with National Institute on Aging Genetics of Alzheimer’s Disease Data Storage Site (NIAGADS) GenomicsDB, a database that provides genetic and functional evidence for AD, to allow researchers cross‐reference other public resources (e.g., dbSNP, ClinVAR, ENCODE, Roadmap), and view functional evidence available for each genetic variant or gene.ConclusionsADVP is the largest collection of systematically curated, harmonized and comprehensively annotated literature‐derived AD‐associated genetic variants. This current ADVP collection contains genetic findings from more than 60 cohorts and >200 studies across a variety of populations including Caucasians, Hispanics, African‐Americans, and Asians. Currently, ADVP contains ∼7,000 AD‐association records corresponding to over 913 unique loci, 1803 unique genetic variants and 951 associations published in multiple studies. ADVP is freely accessible at http://advp.niagads.org.
Effects of acute exercise on functional connectivity in young and older adults
Authors: Goerlich Katharina S. , Xin Yuanyuan , van Asselt Manon , Thioux Marc , Renken Remco , Aleman André 
Published: December 2020

AbstractBackgroundPhysical activity has protective effects on cognition and brain health. Regular exercise contributes to better cognition, promotes functional and structural brain changes, and may even reverse age‐related decline to some extent. However, the effects of a single session of acute exercise on functional connectivity are currently unclear.MethodThe study sample comprised 59 healthy participants, 31 young adults (mean age: 22.3; 8 females) and 28 older adults (mean age: 55.8; 9 females). During their first visit, participants performed a submaximal exercise on a bicycle ergometer to measure their fitness level. During the second and third visits, participants took part in two counterbalanced MRI sessions: an Exercise session and a Relax session. In the Exercise session, participants received a 10‐minute resting‐state scan, followed by a 15‐minute period of aerobic exercise. After the exercise, participants received the second resting‐state scan. For the Relax session, the exercise was replaced by a 15‐minute rest period. Data analysis was performed in SPM8. For the functional connectivity (FC) analysis, 30 seeds were selected from the brain’s major functional networks and relevant subcortical regions. Seed2voxel FC was computed as Pearson’s correlation and transformed to Fisher’s Z. A cluster‐level FEW correction p < 0.05 was applied. Effects of acute exercise on FC were tested across and between the two groups using within‐subject ANOVAs controlling for fitness level and scan order. In addition, correlations and interactions were calculated between fitness level and exercise effects on rsFC.ResultAcross groups, acute exercise was associated with decreased FC of the caudate and the amygdala to the pre and postcentral gyrus. Significant group differences were observed for the putamen and intraparietal sulcus, PreCG and superior frontal gyrus: exercise effects on FC between these regions were significantly larger in young compared to older adults. A significant interaction effect between fitness level and group was found for FC of NAcc‐PCC/Precuneus, with a positive association in young individuals and a negative association in older individuals.ConclusionEven a single session of acute exercise affects functional connectivity in neural networks involved in motor processing and motivation. This relationship is different for young compared to older individuals.
Transcranial magnetic stimulation distinguishes patients with behavioral variant fronto‐temporal dementia from primary progressive aphasia patients
Authors: Lorenzo Francesco Di , Motta Caterina , Bonnì Sonia , Assogna Martina , Caltagirone Carlo , Martorana Alessandro , Koch Giacomo 
Published: December 2020

AbstractBackgroundIn the recent years the use of neurophysiological techniques, combined with other clinical and neuroimaging biomarkers, allowed to further deepen physiopathological mechanisms of neurodegeneration. Fronto‐temporal Dementia (FTD) patients showed an impairment of intracortical circuits investigated with SICI/ICF and LICI protocols, while there is a normal activity of central cholinergic circuitry (investigated with SAI protocol), reflecting the relative sparing of cholinergic system in this disease. In the current work we aimed to determine whether a transcranial magnetic stimulation (TMS) multiparadigm approach can be used to distinguish the behavioral variant of frontotemporal dementia (bvFTD) from non fluent variant of Primary Progressive Aphasia (nfPPA)Method30 patients with bvFTD and 30 nfAPP patients have been enrolled for this study. Paired‐pulse TMS was used to investigate short‐interval intracortical inhibition (SICI) and facilitation (ICF), long‐interval intracortical inhibition (LICI) , and short‐latency afferent inhibition (SAI) to measure the activity of different intracortical circuits in all the participants to the study. We also tested Long‐term Potentiation (LTP) cortical plasticity with iTBS protocol. All the patients underwent an extensive neuropsychological evaluation, MRI and CSF sampling.ResultbvFTD patients exhibited a deficit of SICI, consisting in a disinhibition, while on the other hand nfPPA patients had a weakened ICF resulting in a weakened facilitation. No difference was observed for SAI, reflecting the sparing of cholinergic neurons for both nfPPA and bvFTD patients. bvFTD patients showed a deficit of LICI evident at 100 msec, expression of an impairment of GABA‐B receptors, resulting in a disinhibition of the MEP compared to nf‐PPA. bvFTD patients had a weakened iTBS after effects, oppositely to nfPPA patients that showed the expected LTP‐like cortical plasticity.ConclusionIntracortical circuitry investigation and iTBS protocol showed clear differences among bvFTD patients and PPA, probably reflecting distinct phisiopathological mechanisms. TMS is a noninvasive procedure able to distinguishes between different variants of FTD. These preliminary findings pave to way for a more spread use of neurophysiological techniques in the study and management of neurodegenerative disease such as FTD, not just for better understanding of phisiopathological mechanisms of disease but also in case of monitoring of therapeutical efficiency.
Hypercholesterolemia accelerates Aβ deposition in regions associated with early amyloidosis
Authors: Souza João Pedro Ferrari , Povala Guilherme , Brum Wagner Scheeren , De Bastiani Marco Antônio , Pascoal Tharick A. , Benedet Andréa Lessa , Therriault Joseph , das Ros Lucas U. , Bieger Andrei , Rosa‐Neto Pedro , Zimmer Eduardo R. 
Published: December 2020

AbstractBackgroundHypercholesterolemia is a well‐established risk factor for developing Alzheimer's disease (AD). Mechanisms underlying this relationship, however, are still unclear. Recent experiments have reported conflicting findings regarding the relationship between amyloid‐beta (Aβ) and cholesterol. While in vitro studies have shown that cholesterol accelerates Aβ aggregation, an epidemiological investigation demonstrated that total serum cholesterol is not associated with Aβ load. Nevertheless, it is still unclear whether total serum cholesterol affects Aβ deposition in the human brain. Here, we aimed to assess whether high levels of total serum cholesterol are associated with the rate of Aβ aggregation in the brain. We hypothesized that high total serum cholesterol levels could accelerate cerebral amyloidosis of non‐demented subjects.MethodWe selected 207 non‐demented – cognitively unimpaired and mild cognitive impairment – participants from Alzheimer's Disease Neuroimaging Initiative (ADNI) who had available data for baseline cholesterol and longitudinal amyloid PET scans with [18F]AV45. Subjects were divided into two groups regarding their total serum cholesterol levels, being classified as normal (<200mg/dL; n=158) or abnormal (>200mg/dL; n=107). We performed a voxel‐wise general linear modelling to assess Aβ load differences between groups at baseline. Then, a longitudinal comparison was carried out to evaluate the rate of Aβ deposition in 4 years, calculated as "(IMAGE4_YEARS ‐ IMAGEBASELINE)x100/IMAGEBASELINE". Age, gender, APOEε4, cholesterol treatment and diagnostic group were used as covariates.ResultNo differences were found in Aβ load at baseline. By contrast, we observed a significantly higher rate of Aβ accumulation for the abnormal group in brain regions associated to early amyloidosis, including lateral temporal (peak t(200) = 4.498, p<0.0001) and parietal (peak t(200) = 4.504, p<0.0001) lobes, over a 4‐year period when compared to the normal group (Figure 1).ConclusionOur findings suggest that serum cholesterol dysmetabolism could influence cerebral Aβ aggregation. In addition, our analysis points to a potential communication between central and peripheral cholesterol compartments (perhaps intensified by hypercholesterolemia‐related inflammation). Also, it corroborates with the hypothesis that higher serum cholesterol levels accelerate the process of brain amyloidosis, stressing the need for further investigation on the mechanisms involved in this process.
Early developmental abnormalities in hippocampal synapse distribution in a mouse model of Alzheimer’s disease
Authors: Ray Ajit , Bernhard Sarah M. , Kuljis Dika A. , Bruchez Marcel P. , Barth Alison L 
Published: December 2020

AbstractBackgroundAlzheimer’s disease (AD) has long been described as a disease arising from progressive loss of synapses and cell death. While this is certainly true for the late stages of AD when patient present with clinical symptoms, it has increasingly become a focus of research that early AD may be paradoxically characterized by hyperexcitability and hyperactivity of neurons, specifically in hippocampal CA1 pyramidal neurons. In this study using a transgenic animal model of AD, we investigated whether an alteration in input‐specific synapse numbers could explain this early hyperactivity.MethodB6C3‐Tg(APPswe,PSEN1dE9) mice (APP/PS1) and wild‐type littermates of different ages and both sexes were injected with our novel pan‐synaptic labeling reagent (AAV1‐FAPpost) (Kuljis et al, 2019) in the dorsal hippocampal CA1 region. Labeled pyramidal cells were reconstructed and quantitative synaptic analysis across dendritic compartments was performed.ResultEven at postnatal day 21, CA1 pyramidal neurons from mutant mice showed an increase in the number of medial apical synapses (site for CA3 inputs) and a decrease in distal apical tuft synapses (site for entorhinal inputs), that may persist through adulthood. Proximal apical and basal synapses remained unaffected. Similar analysis in aged transgenic animals (13‐14 months) showed a uniform loss of synapses across all compartments.ConclusionThe compartment‐specific increase in CA3 to CA1 synapses during early development suggests that APP/amyloid‐β may be associated with abnormal synapse formation or stabilization. This increase in excitatory connectivity is consistent with hippocampal hyperexcitability that has been described in preclinical AD. This aberrant increase in CA3 may arise to compensate for the loss of entorhinal inputs and delay the onset of behavioral deficits. Our study demonstrates how AD pathology may progressively damage neural circuit function by inducing primary synaptic deficits and aberrant compensatory reweighting of other synaptic connections.