bluuebunny/crossref_metadata_2025_split huggingface dataset:
Latin American Older people and neuropsychiatric symptoms: a mini‐systematic review of effects of COVID‐19 Pandemic
Authors: URAZAN JUAN CAMILO , Padilla Nubia Esperanza , Borda Miguel German , Pinilla Jonnathan , Fernandez Marcelo Abraham Gaete , Fan Marcela Veliz 
Published: December 2021

AbstractBackgroundEnding December 2019, the world had to face to COVID‐19. Latin America and the Caribbean suffered the effects where the contiguous and the number of deaths has been significant. Studies indicate that older adults with some degree of cognitive impairment are at greater risk of worsening their cognitive status and mental health, for this reason it’s exposed that social isolation and loneliness has harmful effects on the health of this population. This mini‐review inquires on the effects of COVID‐19 due to social isolation on neuropsychiatric symptoms (NPS) in Latin American older adults with and without dementia.MethodA search was carried out in PubMed, SCOPUS, and ScienceDirect identifying all articles published up to July 31, 2021 using the keywords “social isolation”, “lockdown”, “quarantine”, “COVID‐19”,, “neuropsychiatric symptoms ”, “neurobehavioral”, “dementia”,“ mild cognitive impairment ”,“ Older People ”, “aging”, “elderly”. Two independent reviewers screened and selected appropriate articles and a third researcher helped resolve disagreements. The selected articles met the following criteria: written in English, Spanish or Portuguese, original article; focused on elderly subjects, articles that provided information on the NPS effects in Latin American populations during the COVID‐19 pandemic. The review was based on the PRISMA Statement and used the SIGN criteria.ResultFrom 61 articles recovered from electronic databases (PubMed, Science Direct and Scopus) 10 of them were chosen for this review. The majority of the articles reported in a general way a negative impact on the mental health of the population in Latin America. They referred to a significant increase in the anxiety and depression symptoms. The majority of the articles were studies developed in Brazil, Argentina and Chile.ConclusionThe COVID‐19 has shown a negative impact on the mental health of older adults. Latin America is a region with important socio‐sanitary problems which increase the impact of the pandemic in SNP, especially in older adults. It's necessary to increase the studies in Latin America that glimpse the real situation in the region.
Senescence biomarkers in adults and elderly with Down syndrome
Authors: Cordeiro Augusto Magno Tranquezi , Bram Jessyka Maria de França , Talib Leda Leme , Forlenza Orestes Vicente 
Published: December 2021

AbstractBackgroundThe Down syndrome (DS) is a genetic disturb caused for the trisomy of chromosome 21. It is the most common cause of intellectual disability, in addition DS accelerates aging and others development and health problems. Some pathological aspects, common to DS with dementia and Alzheimer disease (AD) suggest common pathogenic aspects. This study aims to investigate biomarkers related to cellular aging and their interrelationship with pathological markers of AD in adults and elderly individuals with DS by determining the expression of apoptotic pathway proteins: β‐catenin plays a role int the cell adhesion, cell survival and cell proliferation, in addition it is a key factor in the Wnt pathway. The activation of Wnt/β‐catenin pathway can protect against neurotoxic effects caused by accumulation of β‐amyloid peptide and the phosphorylation of Tau protein, two neuropathological hallmarks in the AD. The Bcl‐2 protein prevents cell death a promoting the cell survival. The tumoral protein P53 functions in the conservation and stability of DNA. It is normally activated in response of cellular stress, acting in the cell cycle, apoptosis, DNA repairing and the cell metabolism.MethodProteins expressions were measured in platelets from non‐medicated older adults with DS (n=37), and healthy adults and older adults (n=28) by western blotting. The samples were analyzed in duplicate and normalization was done using β‐actin as control.Resultβ‐catenin and P53 expressions were higher in DS samples (p=0.001 and p=0.04 respectively). We found a higher expression of Bcl‐2 in healthy control samples (p=0.05).ConclusionWe concluded that the increased expression of β‐catenin and P53, in addition with the decrease levels of Bcl‐2 might indicate a deregulation in the mechanisms responsible for the cell survival process. It is possible to speculate that these changes are related to the increase in cellular stress related to DS.
High‐content screening of Alzheimer's disease genetic risk factors based on synaptic density analysis
Authors: Coulon Audrey , Mendes Tiago , Kilinc Devrim , Dumont Julie , Chapuis Julien , Lambert Jean‐Charles 
Published: December 2021

AbstractBackgroundSynaptic loss is one of the earliest pathological hallmarks and the strongest marker of cognitive decline in Alzheimer’s disease (AD). A strong genetic predisposition is linked to AD, and genome‐wide association studies have pointed out hundreds of genes associated with the risk of developing the disease. With this background, our objective is to develop a cell‐based screen to assess the impact of each genetic risk factor on synaptic density.MethodWe screened a lentiviral shRNA library targeting 200 AD genetic risk factors using primary rat hippocampal neurons in 384‐wells plates. Immunofluorescence was performed to reveal pre‐ and post‐synaptic compartments and the neuronal network. Synaptic connectivity was then assessed through high content analysis by assigning each post‐synaptic structure to the nearest pre‐synaptic structure using Columbus and Matlab software.ResultWe identified several AD risk genes which positively or negatively impacted synaptic density in our model.ConclusionWe have developed a high‐content screening approach which allows us to define the genetic risk factors that are involved in the pathophysiological synaptic dysregulation observed in the early stages of AD.
Resting‐state EEG gamma power and coherence might be an indicator of hyperexitability in patients with early‐onset Alzheimer’s disease
Authors: Fide Ezgi , Yerlikaya Deniz , Yener Gorsev 
Published: December 2021

AbstractBackgroundEarly‐onset Alzheimer’s disease (EOAD) is characterized by disease onset age (<65 years) and non‐amnestic symptoms at the initial stage. Disease course is different from the late‐onset AD (LOAD) in terms of pathology, neuropsychological manifestations and topography of electrophysiological changes. Present study aims to investigate resting state gamma power and connectivity changes in patients with EOAD compared to healthy controls.MethodThe study included 24 individuals with CSF‐proven EOAD (who met the NIA‐AA diagnostic criteria, McKhann et al., 2011) and demographically matched 24 healthy controls. Four minutes of eyes closed resting state EEG was recorded. Artifact‐free six‐second epochs were obtained. Power and coherency were measured for the total gamma (30–48Hz), gamma‐1 (30‐35Hz), gamma‐2 (36‐40Hz), and gamma‐3 (41‐48Hz). Imaginary part of coherency (ICoh) and maximum absolute values were calculated for intra‐hemispheric, inter‐hemispheric and midline electrode pairs.ResultFFT analysis showed higher gamma‐2 [F(1,46)=4,732,p=0.032], and gamma‐3 [F(1,46)=4,158,p=0.047] power in the EOAD group compared to controls. In the coherence analysis, the EOAD group had higher gamma‐2 inter‐hemispheric ICoh values than controls [F(1,46)=5.473;p=0.024]. The total intra‐hemispheric gamma values of the EOAD group were higher in the F8‐TP8 pair, but lower in the P8‐O2 and F4‐C4 pairs compared to controls [F(11,506)=1.901;p=0.037]. Intra‐hemispheric gamma‐2 values of the EOAD group were higher in the F8‐TP8 pair, but lower in the C3‐O1 pair [F(11,506)=2.207;p=0.031]. Midline gamma‐1 ICoh values were lower in the EOAD group than controls [F(1.46)=8.352;p=0.006].ConclusionTo our knowledge this is the first study to examine resting state gamma changes in individuals with CSF proven EOAD. Increased gamma power and connectivity in patients with LOAD (Başar et al., 2016,2017; van Deursen et al., 2008,2011) and Parkinson’s disease dementia (Pal et al., 2020) were reported. Increased power and connectivity were thought to reflect shared tau pathology between brain regions (Franzmeier et al., 2019). Literature provides evidence for hyperexcitability due to increased glutamate in AMPA and NMDA receptors in patients with AD (Um et al., 2012). Our results from CSF‐proven EOAD patients suggest that gamma power and connectivity might be good indicators of hyperexcitability in AD.
Development and Validation of PEG‐PCL Based Nanoformulation of Rosiglitazone and Evaluation of its Brain Selectivity in Mice Model of Alzheimer’s disease
Authors: K C Sarathlal , Kakoty Violina K , Taliyan Rajeev 
Published: December 2021

AbstractBackgroundType‐2 Diabetes Mellitus and insulin resistance increases the risk of Alzheimer’s disease (AD). Recent studies highlighted the role of peroxisome proliferator‐activated receptor‐gamma (PPAR‐γ) in modulation of AD. This study was designed to investigate the effect of rosiglitazone alone or in its nanoformulated form for an effective drug delivery in mice model of AD.MethodAD mice model was developed by intracerebroventricular (ICV) administration of streptozotocin (STZ). PEG‐PCL polymer was synthesized using ring opening polymerization of caprolactone with methoxy‐PEG as a macroinitiator and stannousoctoate as catalyst. Nanoformulation of rosiglitazone was developed using emulsion‐diffusion‐solvent evaporation method. Nanoformulation was evaluated by Scanning electron microscopy, particle size analyzer and HPLC method. Cognitive functions were evaluated by passive avoidance task, object recognition task and Morris water maze test. Amyloid beta (Aβ) and phosphorylated tau (p‐tau) level were assessed by ELISA, level of oxidative stress and pro‐inflammatory cytokines like tumor necrosis factor‐α (TNF‐α) and interleukin‐6 (IL‐6) were measured in hippocampus homogenates and the expression level of CREB, BDNF, GDNF, NGF were assessed by RT‐PCR method.ResultThe rosiglitazone nanoformulation was observed within a range of 70±10 nm in size and the entrapment efficiency of rosiglitazone was 70±5%. The ICV‐STZ mice showed significant features of cognitive abnormalities. The mice treated with rosiglitazone and its formulation improved cognition, attenuated the elevated level of Aβ and p‐tau along with pro‐inflammatory cytokines‐TNF‐α and IL‐6 and oxidative stress was altered when compared with disease control animals. Moreover, these changes occurred concurrently with an increased expression level of BDNF, GDNF and NGF.ConclusionNanoformulation of rosiglitazone imparted significant neuroprotective efficacy with greater amounts being observed in the brain at a lower dose compared to its free form.
Human Herpesvirus detection and identification in postmortem brain tissue of patients with Alzheimer's disease
Authors: Gomez Johana , Villegas‐Lanau Carlos Andrés , Mesa Ana 
Published: December 2021

AbstractBackgroundThe etiology of Alzheimer’s disease (AD) is not clear yet. One of the hypotheses in this regard is the participation of infectious agents in the origin of this neurodegenerative disease. Different viruses, mainly those that cause latent infections such as some of the Herpesviridae family, have been the most involved. The aim of this study was to detect and identify herpesviruses in postmortem brain tissue of patients with AD.Methodfrozen brain tissues from patients diagnosed with AD (n=22) and from healthy individuals (n=10), as a control group, were included. The search and identification of Human Herpesvirus in the tissues was carried out using microarray technology (Axiom™ Microbiome Array, Thermo scientific, USA) and real‐time multiplex PCR.Resultno viruses were detected using the microarray technology; howeverer, using real‐time multiplex PCR, human herpesviruses VHH‐1, VHH‐2 or VHH4 were identified in two samples of patients with AD and one case in the control group.ConclusionBased on the results obtained in this study, it was not possible to establish an association between AD and the presence of viruses. Yet, it is possible that the viruses play a role in the pathogenesis of AD, perhaps in the early stages of this dementia.
Insertion of the Icelandic mutation (A673T) in the APP gene using the CRISPR/Cas9 base editing and Prime editing technologies, a preventive treatment for Alzheimer?
Authors: Tremblay Jacques P. , Tremblay Guillaume , Guyon Antoine , Joël Rousseau , Happi‐Mbakam Cedric 
Published: December 2021

AbstractBackgroundThere is currently no treatment for Alzheimer disease (AD). However, the Icelandic mutation in the APP gene (A673T) has been shown to confer a protection against the onset and development of AD (Jonsson et al. Nature 2012). This single nucleotide mutation in APP exon 16 reduces the cleavage of the APP protein by the beta‐secretase by 40% thus preventing the development of AD even in persons more than 95 years old.MethodOur research group has initially shown that the presence of the A673T mutation in an APP gene reduced the secretion of beta‐amyloid peptides even if there is also a FAD mutation in the gene. This is the case for 14 different FAD mutations.We have also used the CRISPR/Cas9 base editing technology to insert the A673T mutation in the APP gene. We have compared several different cytidine base editor complexes to achieve the most effective and accurate genome modification possible in HEK293T cells and in SH‐SY5Y neuroblastomas. The insertion of the A673T mutation in cells containing the London mutation reduced the secretion of beta‐amyloid peptides.ResultWe have more recently used the Prime editing technology to insert only the A673T mutation without inducing the mutation of other nearby nucleotides. Repeated Prime editing treatment permitted to insert this mutation in up to 64% of the APP gene in HEK293T cells.ConclusionThe insertion of the protective Icelandic mutation in the APP gene using these editing technologies opens a new potential preventive treatment for not only for Familial Alzheimer’s diseases but also for sporadic Alzheimer’s disease.
Functional characterization of hiPSCs‐derived glial cells and neurons from patients harboring a TREM2 loss of function mutation
Authors: Filipello Fabia , You Shih‐Feng , Martinez Rita , Korvatska Olena , Raskind Wendy H , Mahali Sidhartha , Ghezzi Laura , Wandy Beatty , Cella Marina , Piccio Laura , Karch Celeste M. 
Published: December 2021

AbstractBackgroundTriggering receptor expressed on myeloid cells 2 (TREM2) is an innate immune receptor expressed by microglia in the adult brain. Homozygous loss of function TREM2 variants cause a rare leukodystrophy characterized by bone cysts and early‐onset dementia, Nasu‐Hakola disease (NHD). However, despite intense investigation, the role of TREM2 in NHD pathogenesis remains poorly understood.MethodHere, we investigated the mechanisms by which a homozygous stop‐gain TREM2 variant (Q33X), which leads to a truncated TREM2 transcript, contributes to disease pathology in NHD. Human induced pluripotent stem cells (hiPSCs)‐derived microglia (iMGLs), neurons and astrocytes were obtained from two siblings homozygous for the TREM2 Q33X mutation and one non‐carrier sibling.ResultTranscriptomic analysis and biochemical assays revealed that iMGLs from NHD patients display decreased activation, reduced lipid droplet content and defects in lysosomal function compared to related and unrelated controls. These in vitro findings were validated in brain tissues from NHD patients carrying loss of function TREM2 mutations. Strikingly, we observed defects beyond iMGLs. iPSCs‐derived neurons and astrocytes from NHD siblings displayed downregulation of pathways involved in synaptic activation, neuronal development and interferon response compared to the unaffected sibling. These pathways were also observed to be similarly altered in NHD brains. This could be due to the presence of low levels of mutant TREM2 transcripts in iPSC and neural progenitor cells, which may initiate a cascade of events that drives cellular dysfunction beyond microglia.ConclusionThese finding open a new scenario on TREM2 function and reveal that NHD is a complex pathology affecting glial cells and neurons at multiple levels.
Pattern of proteolytic processing of Amyloid Precursor Protein in Down syndrome
Authors: Bram Jessyka Maria de França , Cordeiro Augusto Magno Tranquezi , Talib Leda Leme , Carvalho Claudia Lopes , Gattaz Wagner Farid , Forlenza Orestes Vicente 
Published: December 2021

AbstractBackgroundCurrently, it is estimated that 1 in 800 live births worldwide has Down syndrome (DS). In addition to the relationship with intellectual disability, DS is directly associated with a group of clinical manifestations resulting from premature aging, and may present patterns of comorbidities similar to those found in the elderly. Therefore, together with the greater number of years lived, there is an increased risk of developing Alzheimer's disease (AD) in DS, especially with regard to the interaction between pathogenic mechanisms related to cerebral amyloidogenesis and factors inherent to premature aging. Thus, this study aimed to investigate biological markers of AD in peripheral blood samples from adults and elderly individuals with DS and to compare them with individuals with normal karyotype, stratifying the groups according to the presence or absence of cognitive impairment.MethodA total sample of 123 individuals was recruited. The experimental group consisted of 31 adults and elderly individuals with DS. Two comparative groups were categorized according to euploid individuals (EU), being 23 elderly with AD (EUAD) and 69 adults with normal cognition (EUNC). The DS group was subclassified according to the occurrence of cognitive decline, DS without evidence of cognitive decline (DSNC) and DS with cognitive decline (DSAD). AD biomarkers were determined in platelets, including the Amyloid Precursor Protein ratio (APPr), established by the ratio between the 130‐ and 110kDA secreted peptides (sAPP), as well as the protein expression of APP‐secretases α (ADAM‐10), β (BACE‐1) and γ (PSEN1).ResultThe comparison between DSNC vs. EUNC, showed lower protein expression of APP secretases among individuals with DS. When observed groups with cognitive decline (i.e., DSAD vs. EUAD), the DSAD group showed lower expression of APP130 and 110kDa and BACE1 fragments, as well as increased levels of APPr compared to EUAD. It was also observed a 2.5‐fold decrease expression of APP130 in SDAD, compared to SDNC.ConclusionThese results demonstrate that people with DS may show different expression patterns of proteins involved in the amyloid cascade, detectable even in the absence of cognitive decline. However, more analysis is needed for these data to be confirmed.
Systems genetic dissection of Alzheimer’s disease brain gene expression networks
Authors: Zhao Pinghan , Mangleburg Carl Grant , El Fadel Omar , Lee Anh , Amoh Bismark , Sai Marella Aditi , Al‐Ramahi Ismael , Botas Juan , Shulman Joshua M. 
Published: December 2021

AbstractBackgroundAlzheimer’s disease (AD) is the most prevalent cause of dementia. Large RNA‐Sequencing data sets have provided detailed molecular profiles of AD, but they cannot differentiate causal vs. non‐causal gene expression changes.MethodWe combined bioinformatic prioritization of human data with genetic screens in Drosophila melanogaster to identify human brain transcriptional changes that exacerbate or ameliorate neurodegeneration induced by Tau or amyloid‐β (Aβ), the proteins which form the hallmark pathologic aggregates that define AD. First, we used large, AD‐associated coexpression networks derived from Accelerating Medicines Partnership (AMP)‐AD human brain RNA‐Seq data to nominate candidate AD drivers based on multiple bioinformatic criteria. We then tested nominated drivers for modification of Tau‐ or Aβ‐induced neurodegeneration in vivo using a locomotor assay in Drosophila. For one module of our interest, PHGbrown, we analyzed its overlap with published differentially expressed gene (DEG) sets from mouse models to explore its potential functional roles in AD. Finally, we used the L1000 Connectivity Map database of perturbation‐associated gene expression changes to select small molecules which either reverse or promote the implicated AD‐associated gene expression signatures that are causally linked with disease progression.ResultThrough our screen, we identified a module, PHGbrown, with 14 of its 27 prioritized genes (51.9%) significantly modifying Tau/Aβ neurotoxicity in our screen. We integrated our screen data with PHGbrown’s module structure to identify a subnetwork containing genes involved in synaptic function including GRIN2A, GRIN2B, KCNJ6, GABRB2, and GABRB3. This synaptic subnetwork is downregulated in human AD and contains multiple loss‐of‐function suppressors of Tau/Aβ neurotoxicity. Interestingly, PHGbrown shows overlap and concordant down‐regulation with published mouse models of excitotoxicity. Our results suggest that PHGbrown down‐regulation may compensate for excitotoxic injury in AD. Based on in silico analysis of L1000 Connectivity Map data, the protein kinase C inhibitor, Chelerythrine, was identified as a promising “network therapy” capable of promoting PHGbrown down‐regulation and resilience to AD pathophysiology.ConclusionBy integrating human coexpression networks and Drosophila genetic screen data, our results establish a causal chain connecting Tau/Aβ with neurodegeneration through network‐level gene expression changes. We additionally identify candidate drugs targeting causal subnetworks for development of network modulating therapies.
Dementia detection from brain activity during sleep
Authors: Ye Elissa M , Sun Haoqi , Krishnamurthy Parimala V , Lam Alice D , Westover M Brandon 
Published: December 2021

AbstractBackgroundDementia is a growing cause of disability and loss of independence in the elderly, yet remains largely under‐diagnosed. Early detection and classification of dementia may help close this diagnostic gap and improve management of disease progression. EEG sleep patterns have been identified as a potential biomarker to detect Alzheimer’s disease and other neurodegenerative diseases.MethodFrom a dataset of 9834 polysomnograms, sleep architecture and microstructure features such as frequency band powers, EEG coherence, and spindle density were extracted. Patients were labeled as belonging to dementia, mild cognitive impairment (MCI), or cognitively normal (CN) groups based on clinical diagnosis, Montreal Cognitive Assessment (MoCA), Mini‐Mental State Exam (MMSE) scores, Clinical Dementia Rating (CDR) and medications. We trained logistic regression, random forest, and XGBoost models to classify patients into Dementia, MCI, and CN groups.ResultNested cross validation results show an AUC of 0.81 (F1 = 0.76) for binary classification of dementia vs CN groups and a mean AUC of 0.75 (F1 =0.57) for multiclass classification of dementia vs. MCI vs CN groups. REM latency, spindle activity, duration, frequency, slow wave oscillation, delta/alpha band power in wake, N1 theta/alpha band power in N1 were among the top weighted features.ConclusionOur dementia classification algorithms show promise for incorporating dementia screening techniques into routine sleep EEG and providing diagnostic, monitoring, and prognostication capabilities.