bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pharmacological suppression of seizure‐like activity in the PS2APP model of amyloidosis
Authors: Weber Martin , Imperio Jose , Gandham Vineela , Meilandt William , Hanson Jesse E. , Easton Amy E. , Elstrott Justin 
Published: December 2020

AbstractBackgroundSeizure activity is significantly increased in patients with Alzheimer Disease relative to healthy controls. Concurrently, the J20 mouse model of amyloidosis has increased seizure‐like activity, and compounds that lower this activity can lead to cognitive benefits in this model. Here we aim to extend these studies to the PS2APP mouse model of amyloidosis.MethodLocomotor activity was measured for 60 min in C57BL/6J mice with a beam‐break based monitoring system (PAS Open Field, San Diego Instruments) using a between‐subjects design with 9‐10 mice/dose group. EEG/EMG headmounts were implanted into PS2APP mice with amyloid‐beta pathology. Data was recorded for 6h using a Pinnacle Technologies recording system and processed with MATLAB (Mathworks) routines. EEG spikes were detected using a thresholded line‐length algorithm.A within subject crossover‐design was used for vehicle vs. Levetiracetam treatment and data from 13 PS2APP mice was analyzed.ResultLocomotor activity measures showed that an acute dose of 200 mg/kg of the anti‐seizure medication Levetiracetam did not affect activity levels. EEG recordings demonstrated that the frequency of seizure‐like spikes during sleep was increased from 38 spikes/h in 4 months old PS2APP mice to 75 spikes/h in 13 months old PS2APP mice. This measure was reduced by ∼60% in 13 months old PS2APP mice in response to acute treatment with 200 mg/kg of Levetiracetam.ConclusionSeizure‐like activity is increased in patients with Alzheimer’s disease and in mouse models of amyloidosis. Our Levetiracetam studies confirm that pharmacological intervention can normalize seizure‐like activity in PS2APP mice. Medications with different mechanism of action need to be tested for their ability to reduce spike activity and improve cognition in this animal model.Ultimately, it will be important to see if such pharmacological effects translate to humans and if reductions in seizure activity are linked to functional improvements.
Apa I, Taq I and Fok I VDR polymorphisms: Functional effect on mRNA levels of amyloid beta transporters LRP1 and P‐gp in lymphocytes of mild cognitive impairment patients
Authors: Arevalo Nohela , Castillo Daniela , Rogers Nicole , Delgado Carolina , Farías Gonzalo , Behrens María Isabel , SanMartín Carol D. 
Published: December 2020

AbstractBackgroundLRP1 and P‐gp are the major efflux transporters of β‐amyloid peptide (Aβ) across the blood brain barrier and the expression of both transporters is mediated by the vitamin D receptor (VDR). Three single nucleotide VDR polymorphisms (SNPs) Taq I, Apa I and Fok I have been related to mild cognitive impairment (MCI); however, their functional effect on the expression of VDR and its target genes remains unclear.Method76 MCI patients and 133 elderly volunteers were cognitively screened with the Montreal Cognitive assessment (MoCA) and MoCA‐MIS after signing an informed consent approved by the Ethics Committee of Hospital Clínico Unversidad de Chile. The VDR SNPs Apa (rs7975232), Taq (rs731236) and Fok I (rs2228570) were determined by TaqMan SNP genotyping assay. mRNA levels of VDR, LRP1 and P‐gp were evaluated by qPCR.ResultThe C and T alleles of Apa I and Taq I respectively were more frequent in the MCI (p < 0.05); additionally the odds ratio analysis (OR) was significant for both alleles (C allele OR: 1.5 p = 0.049; T allele OR: 1.89, p = 0.0044). There were no significant differences for Fok I polymorphism between the groups. Furthermore, the homozygous CC of Apa I had significantly lower mRNA levels of P‐gp and VDR than the homozygous AA and heterozygous AC (p < 0.05). The carriers of one copy of the C allele (TC) of Fok I had lower mRNA levels of VDR and of both transporters than the homozygous TT (p < 0.005).ConclusionThe C and T alleles of Apa I and Taq I respectively might be risk alleles for MCI, as reported in other populations. In addition, we found that SNPs of the VDR gene are related to the decrease of the mRNA levels of the Aβ transporter P‐gp and the transcription factor VDR.
Amyloid propagation in a sporadic model of Alzheimer's disease
Authors: Huynh Kelly Do , Nguyen Marie Minh Thu , Cheung Alwin , Tran Janine Pham , Nuñez‐Diaz Cristina , Forner Stefania , Martini Alessandra Cadete , Trujillo‐Estrada Laura , Da Cunha Celia , Shahnawaz Mohammad , Soto Claudio , Moreno‐Gonzalez Ines , Gutierrez Antonia , LaFerla Frank , Baglietto‐Vargas David 
Published: December 2020

AbstractBackgroundMost age‐associated neurodegenerative disorders involve the aggregation of specific proteins within the nervous system, as occurs in Alzheimer’s disease (AD). Recent evidence indicates that Aβ can misfold and aggregate into seeds that structurally corrupt native proteins, mimicking a prion‐like process of template protein corruption or seeding. In fact, studies in FAD‐based animal models show that Aβ deposition and cerebral amyloid angiopathy may be induced by intracerebral infusion of brain extracts from AD patients or from aged APP‐transgenic mice. These studies have shown that the characteristic of both the seeding agent and the host influence the pathologic signature of the Aβ seeds. In this regard, the majority of the Aβ‐seeding studies have been done in APP‐transgenic animal models that overproduce APP and/or Aβ. However, it remains to be elucidated whether Aβ deposition can be induced by Aβ seeds in an animal model that does not overexpress APP and produces wild type human Aβ and if these aggregates are similar to the human condition.MethodHere, we used an innovative animal model to better understand the amyloidogenic events that occur in the sporadic form of the disease. Our model, termed hAβ‐KI, expresses wild‐type human Aβ under the control of the endogenous mouse APP gene. Thus, amyloid seeds from AD patients (stage C for amyloid) from the Alzheimer’s Disease Research Center (ADRC) at UCI were administered into 7‐8‐month‐old hAβ‐KI and as positive controls 3xTg‐AD mice were employed.ResultOur findings demonstrated that amyloid seeds can stimulate Aβ aggregations in both models (the 3xTg‐AD and the hAb‐KI). Moreover, we found that Aβ aggregates occur earlier in the 3xTg‐AD vs hAb‐KI and that a longer term of treatment is necessary to accelerate diffusible Aβ pathology in the hAb‐KI mice.ConclusionThis knockin model represents an important first step towards the development of next‐generation animal models that hopefully will provide better predictive outcomes for human patients, which can turn into safe and effective clinical applications.
Effects of 12‐week combined cognitive training and physical activity intervention on cognitive and psychosocial outcomes of Brazilian older adults
Authors: Almeida Mariana Luciano , Glymour M Maria , da Silva Rodrigues Guilherme , Sobrinho Andressa Crystine da Silva , Júnior Carlos Roberto Bueno 
Published: December 2020

AbstractBackgroundCognitive training and physical activity provide mental, social and physical stimulation that may reduce dementia risk. However, there is limited evidence on the benefits of interventions to increase cognitive engagement among healthy elderly. The present study aimed to evaluate the effect of combined cognitive training and physical activity on cognitive function and psychosocial well‐being among healthy middle‐aged and older adults.Method114 adults with age between 50 to 80 years, recruited by advertisements in the local media, were randomized into four intervention arms: 1) cognitive training + physical activity, 2) cognitive training only, 3) physical activity only, or 4) no‐intervention control group. The interventions had 12 weeks of duration with 90 minutes of cognitive training (groups 1 and 2), and 180 minutes of physical activity (groups 1 and 3) per week. Participants were assessed for cognitive performance (MoCA), social support, depressive and anxiety symptoms, at baseline and follow‐up. Data were analyzed through Generalized Additive Models for Location, Scale, and Shape ‐ GAMLSS, controlling for age, sex and years of schooling.ResultMost of the subjects were female, mean age of 64.5 years (SD=7.0), and average schooling of 12.1 years (SD=3.7). After 12 weeks we conclude the follow‐up with 88 participants. Following the intervention, MoCA increased in all groups (Coef=.98, 95%CI=.00;1.95, p<.01). There was no evidence of differences between the intervention groups for MoCA (1x2 p=.99, 1x3 p=.94, 1x4 p=.92, 2x3 p=.97, 2x4 p=.95, 3x4 p=.99). Subjects from group 1 and 2 increased the number of people to provide social support comparing to the control group (Coef=.27, 95%CI=.00;.54, p=.04/ Coef=.27, 95%CI=.00;.55, p=.03). There was no evidence of differences between the intervention groups for social support (1x2 p=.99, 1x3 p=.53, 1x4 p=.20, 2x3 p=.50, 2x4 p=.18, 3x4 p=.88). Depression and anxiety symptoms did not show effects or interactions (p=.73/ p=.68). There was no evidence of differences between the intervention groups for depression and anxiety (1x2 p=.99, 1x3 p=.94, 1x4 p=.92, 2x3 p=.97, 2x4 p=.95, 3x4 p=.99/ 1x2 p=.99, 1x3 p=.76, 1x4 p=.74, 2x3 p=.78, 2x4 p=.76, 3x4 p=.99).ConclusionSocial support showed positive results for combined interventions and cognitive training.
Towards a better understanding of human brain ageing: An RNA sequencing study of neuroinflammatory, neurotransmission‐related and synaptic genes in two key brain regions over the lifespan
Authors: Mohan Adith , Thalamuthu Anbupalam , Mather Karen A. , Sachdev Perminder S. 
Published: December 2020

AbstractBackgroundNeuroinflammation, synaptic function, and neurotransmission are implicated in gene expression studies of human brain aging. We examined 869 genes specific to these 3 pathways using RNA sequencing in 2 age‐critical brain regions of the human brain, the dorsolateral prefrontal cortex (DLPFC) and posterior cingulate cortex (PCC) in a post‐mortem cohort of 67 non‐diseased control individuals aged 36‐103 years.MethodsPost mortem brain tissue was obtained from the Human Brain Collection Core (HBCC), , NIMH (n = 41, mean age 56y, 25 male) and the Sydney Brain Bank (n = 26, mean age 91y, 12 male) with 2 samples (1 each from the DLPFC and the PCC) per control participant. Controls were free of neurological disease at the time of death. Additionally, tissue samples did not meet pathological criteria for neurological or neurodegenerative disease and were stroke free in the regions of interest. RNA extraction and library preparation used standard protocols with rRNA depletion (TruSeq Stranded Ribozero prep). 100 base pair paired end reads were obtained on a NovaSeq S4 (Illumina) with a minimum of 50 million paired reads per sample. Standard bioinformatics pipeline was used to process raw read data into normalised gene expression values. We examined relationship of age with gene expression adjusted for gender, post‐mortem interval and library size using regression analyses corrected for multiple testing. Candidate gene lists were derived from public gene‐ontology databases namely KEGG and PANTHER as well as a previously published set of microglia‐derived genes (Butovsky, et al., 2014).Results320 and 204 genes from our candidate pathways showed significant differential expression with age in the DLPFC and PCC respectively. The majority of these were upregulated with age in both cortical regions. More than 80% of upregulated genes across both regions were neuroinflammation related, and most upregulated neurotransmission genes encoded elements of the glutamatergic transmission. Genes related to synaptic elements were almost exclusively downregulated with age. 151 genes were significant in both regions and followed the same age‐related pattern as above.ConclusionsOur findings support the prominence of neuroinflammation and excitotoxicity as prominent drivers of molecular brain aging. Further network analyses are planned including eQTL analyses.
Novel metrics of semantic fluency as preclinical markers of cognitive impairment
Authors: Vonk Jet M.J. , Geerlings Mirjam I. , Qian Carolyn L. , Schupf Nicole , Mayeux Richard , Brickman Adam M. , Manly Jennifer J. 
Published: December 2020

AbstractBackgroundAccurate identification of the preclinical phase of Alzheimer’s disease (AD) is important for intervention and timely diagnosis. Some researchers suggest that this phase is only detectable using biomarkers, but these are expensive and/or invasive. Because not all biomarker‐positive individuals develop AD‐dementia and cognitive impairment is at the core of this diagnosis, there is a critical need for sensitive, low‐cost, and high‐access cognitive markers. This study investigated how novel item‐level metrics of semantic fluency—naming as many animals in one minute—uniquely relate to 1) memory decline and 2) mild cognitive impairment (MCI).MethodTo investigate the effect of traditional and novel metrics of semantic fluency on both outcomes in a diverse community‐based cohort followed up to 24 years (mean age=75), we used 1) growth curve models of memory decline (n=534, modeled up to 4 visits), and 2) Cox regression models of time to incident MCI (n=349, free of MCI at baseline and >1 visit). Each word’s lexical frequency value—how often a word occurs in daily language—was derived from SUBTLEXus. Models with total number score were compared to two novel metrics: ratio of mean frequency:number and mean frequency of the lowest 10 frequency words. Covariates included age, sex/gender, education, race/ethnicity, recruitment wave, and all other neuropsychological scores.ResultsBoth novel metrics of ratio (standardized B=‐.049, p=.003) and lowest 10 (B=‐.024, p=.003) predicted rate of memory decline over and above other neuropsychological tasks, while total number did not (B=.015, p=.055). The novel metrics were also predictive of time to incident MCI over and above other neuropsychological tasks (HR ratio =1.43, HR lowest 10=1.54, both p<.05), while total number was not (HR=.74, p=.141).ConclusionNovel item‐level metrics of semantic fluency predicted rate of memory decline and incident MCI over and above other neuropsychological tasks, while the traditional fluency score did not. Item‐level data hold a wealth of information that could detect cognitive symptoms in the preclinical phase of dementia beyond our current neuropsychological measures. Future research should investigate more item‐level data to identify optimal metrics that can be used as clinical tools and aid selection of high‐risk individuals for intervention.
Norvaline regulates glucose metabolism and insulin pathway in the brains of Alzheimer’s disease mice
Authors: Polis Baruh , Gurevich Vyacheslav , Samson Abraham O. 
Published: December 2020

AbstractBackgroundAlzheimer’s disease (AD) is an insidious, progressive, neurodegenerative disorder and the leading cause of dementia. The disease development is followed by the gradual deposition of amyloid plaques and neurofibrillary tangles in the brain; however, converging evidence points to severe metabolic dysfunction as a cause and a key hallmark of AD. Late‐onset form AD, in particular, is characterized by a clear metabolic signature and caused by numerous etiological factors. Severe brain insulin signaling impairment and a decline in glucose metabolism are important metabolic characteristics of AD. Subsequently, positron emission tomography (PET) with radioactive glucose tracers is a well‐established non‐invasive method for early detection of AD symptoms and a treatment efficacy monitoring tool. Additionally, recent data indicate a critical role of the brain insulin resistance in AD pathogenesis. Accordingly, targeting insulin signaling attracted much attention in the context of AD drug development.MethodConverging evidence points to arginase inhibition with norvaline as a promising approach to treat various metabolic disorders, including AD. Here, we use 3×Tg‐AD mice, which show age‐dependent brain insulin signaling abnormalities and reduction in brain insulin receptor levels followed by severe brain energy metabolism alterations, to evaluate the effects of norvaline on glucose metabolism in vivo.ResultWe utilize 18F fluorodeoxyglucose whole‐body PET and demonstrate a significant treatment‐associated increase in glucose uptake by various organs, including the brain. Additionally, we apply an advanced proteomics assay to explore the molecular mechanisms underlying the effects of norvaline on glucose brain uptake.ConclusionOur findings suggest that norvaline interferes with AD pathogenesis and presents a promising agent for clinical evaluation.
Progression modelling of cognitive decline and associated FDG‐PET imaging features in Alzheimer’s disease
Authors: Prosser Angus , Evenden Dave , Holmes Robin , Kipps Christopher 
Published: December 2020

AbstractBackgroundPrognosis for Alzheimer’s disease is difficult, with rates of disease progression varying widely. Despite the extensive use of clinical dementia severity assessment scales to determine dementia diagnosis and to monitor progression, there is no consensus on which imaging factors may accurately predict future decline trajectories on these measures. Determination of baseline imaging patterns that are related to slower, or faster, decline rates could be used to identify those at highest risk of worse outcomes and inform care planning.MethodDecline trajectories were estimated from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) dataset which contains clinical, imaging, and biological assessment records for 1,736 patients followed‐up over 8 years at 3, 6, or 12 month intervals. Clusters of similar decline trajectories were identified for patients with relevant baseline fluorodeoxyglucose positron emission tomography (FDG‐PET) imaging data (N=530) using mini‐mental state examination (MMSE), clinical dementia rating sum of boxes (CDR‐SB), Alzheimer’s disease assessment scale (ADAS‐13), and functional activities questionnaire (FAQ) assessment scores. Decline trajectories allocated to slow, intermediate, and fast clusters were further analysed to find significant associations with PET imaging features using statistical parametric mapping (SPM12).ResultWhen compared to cognitively normal non‐decliners, slow, intermediate and fast cluster groups showed similar topographic patterns of hypometabolism on FDG‐PET for all four clinical assessments (p<0.05 family‐wise error corrected). Slow progressors showed focal hippocampal hypometabolism, which extended into parietotemporal, inferior parietal and precuneal regions for intermediate progressors. Fast progressors showed more extensive hypometabolism in similar regions with additional superior frontal hypometabolism. Although locational deficits were similar on cognitive measures for decline groups, CDR‐SB showed the greatest hypometabolism extent for slow progressors, followed by FAQ, then ADAS‐13, with MMSE showing the least.ConclusionOur results suggest a single pattern of pathological progression of functional degeneration in Alzheimer’s disease, with slow, intermediate and fast progressors at different time points on the same decline trajectory. This progression begins with focal medial temporal regional abnormalities, extending to parietotemporal, inferior parietal and precuneus regions, before finally involving the superior frontal lobe. CDR‐SB was the most sensitive in detecting slow progressor abnormality, with MMSE being the least sensitive.
Telomere length, brain tau deposition and cognitive decline: Two‐year follow‐up study
Authors: Byun Min Soo , Yi Dahyun , Lee Jun Ho , Lee Jang‐Seok , Lee Hyun‐Seob , Kim Yu Kyeong , Lee Yun‐Sang , Lee Dong Young 
Published: December 2020

AbstractBackgroundTelomere length (TL) is known to be associated with aging and various age‐related diseases. However, previous studies on the relationship between the TL and Alzheimer’s disease (AD) yielded inconsistent results, and the association between TL and in vivo AD pathologies such as cerebral beta‐amyloid (Aβ) and tau deposition remains unclear. We investigated whether TL is related to in vivo AD pathologies and predicts future cognitive decline.MethodTotal 132 older adults recruited from the Korean Brain Aging Study for the Early Diagnosis and Prediction of Alzheimer’s Disease were included for analysis. For all participants, absolute TL values (aTL) were measured by a quantitative PCR method using DNA extracted from whole blood at baseline, as aTL can provide more direct comparison between experiments and laboratories compared to traditional TL assays. Global PiB retention measured 11C‐PiB‐PET and global tau deposition in the regions corresponding to Braak stages measured by 18F‐AV‐1451 PET were used in this study. For clinical outcome, conversion of clinical diagnosis and change of MMSE score assessed at baseline and 2‐year follow‐up was used.ResultAmong 132 older adults, 71 of them were cognitively normal and 51 of them were cognitively impaired (39 MCI and 22 AD dementia) at baseline and total 20 individuals converted to MCI or AD dementia during 2 year follow‐up period. No significant group difference in aTL was observed between diagnostic groups at baseline. However, aTL at baseline was significantly longer in converters (N=20) compared to non‐converters (N=112) even after adjusting age, sex, APOE4 positivity and baseline diagnosis. In addition, the difference of MMSE score between baseline and 2‐year follow‐up showed positive association with baseline aTL after adjusting age, sex, education, APOE4 and baseline diagnosis. With regard to in vivo AD pathologies, baseline aTL had a significant positive association with global tau deposition, but not with global Aβ deposition.ConclusionOur finding suggests that longer TL relates to greater tau deposition in brain and more rapid cognitive decline in older adults. Further studies to elucidate mechanism underlying the association of TL with tau deposition and cognitive decline will be necessary.