bluuebunny/crossref_metadata_2025_split huggingface dataset:
SARS‐CoV2 Nucleocapsid Protein induces Tau pathological changes in the mouse hippocampus
Authors: Orsini Franca , Bosica Marco , De Paola Massimiliano , Martucci Annacarla , Pascente Rosaria , Arancio Ottavio , Fioriti Luana 
Published: December 2023

AbstractBackgroundNeurologic manifestations are emerging as an immediate consequence of SARS‐CoV2 infection, the etiologic agent of COVID19. Although little is known about the long‐term consequences of SARS‐CoV2 infection, there is the possibility that infection may trigger long‐term neurological effects. Exposure to pathogens in fact triggers inflammation in the brain and exacerbates Tau pathological changes in animal models of Alzheimer disease. Reports of the presence of SARS‐CoV2 in the brains of subjects with COVID19 are emerging and a study in brain organoids revealed that SARS‐CoV2 alters the phosphorylation and distribution of Tau in infected neurons, but the mechanisms are currently unknown. We hypothesize that these pathological changes are due to recruitment of Tau into stress granules (SG) operated by the Nucleocapsid protein (NP) of SARS‐CoV2.MethodTo address whether exposure to SARS‐CoV2 may predispose to develop dementia, we investigated whether NP interacts with Tau and induces hyperphosphorylation and aggregation of Tau in human iPSC cells and hippocampal neurons in vivo. We tested whether NP interacts with Tau by co‐immunoprecipitation experiments. Mechanistically, we tested whether posttranslational modification of NP and Tau by SUMO2 modulates their distribution in SG and their pathological interaction. We expressed NP for 2 months, with or without SUMO2, in the hippocampus of 6 months old wild type and JNPL3 mice, before performing Y‐maze. After behavioral assessment, the mice were sacrificed and brains were isolated to perform biochemical and immunofluorescence analyses.ResultWe found that NP and Tau co‐localize and physically interact in human cells. We also found that NP induces hyperphosphorylation of Tau and reduces the amount of synaptic proteins in neurons. This is also paralleled by a reduction in the cognitive abilities of mice infected with NP in their hippocampus. Finally we found that modulation of SUMOylation dramatically affects SG induced by NP in cells, Tau hyperphoshorylation, as well as cognitive performance in mice infected with NP.ConclusionOur data demonstrate that NP induces pathological changes in cells and animals expressing wild type Tau, and aggravates the pathology in neurons expressing mutant forms of Tau, both in vitro and in vivo. Moreover we demonstrate that SUMO2 conjugation ameliorates NP‐induced Tau pathology.
Insights into Neurocognitive Sequelae of COVID‐19 Infection from Studies of Brain Organoids
Authors: Ng Jing Han , Tan Eng King 
Published: December 2023

AbstractBackgroundCOVID‐19 has been associated with chronic neurocognitive changes which persist after resolution of the acute infection. Brain organoids composed of different neuronal cell types serve as a useful model to evaluate the underlying effects of SARS‐CoV‐2 infection to the brain and facilitate insights into the neurocognitive sequelae of COVID‐19.MethodA review of studies which used brain organoids to evaluate the effects of COVID‐19 was conducted. The studies were identified from the PubMed/MEDLINE database using the search terms “SARS‐CoV‐2” or “COVID‐19” in combination with “organoid” or “brain” or “3D” or “iPSC”. Articles published in English between 1 Jan 2020 and 31 Mar 2023 were included.ResultWe identified a total of 16 studies which used brain organoids to study SARS‐CoV‐2 neurotropism and downstream effects. Although SARS‐CoV‐2 was able to infect neurons, the extent of neurotropism was limited. Instead, choroidal epithelial cells and glial cells including, astrocytes and microglial, demonstrated significant susceptibility to SARS‐CoV‐2 infection. Furthermore it was observed that certain downstream effects of SARS‐CoV‐2 infection were associated with pathways seen in neurodegenerative diseases like Alzheimer’s Disease (AD). These included findings of reactive astrogliosis, impairment of glutamate and choline transporters, microglial‐mediated synapse loss, increased pTau expression and beta amyloid protein accumulation. Overall, the studies suggested that the neurocognitive manifestations of COVID‐19 may be contributed by neuroinflammatory processes and pathways that are found in chronic neurodegenerative conditions like AD.ConclusionAlthough brain organoid technology remains a relatively new tool, it has provided important insights into the pathophysiology of COVID‐19. The use of “assembloids” to recapitulate interactions between different brain regions and development of high throughput evaluation to analyse transcriptome and epigenome changes of infected brain organoids may be further expanded to allow a better understanding of potential neurodegenerative pathways that may result in neurocognitive changes after a viral infection.
A Virtual Reality Memory Test for Assessing Visuospatial Memory
Authors: Kim Ko Woon , Lee Hyejoo , Choi Jong Doo , Chin Juhee , Lee Byung Hwa , Na Duk L 
Published: December 2023

AbstractBackgroundVisuospatial memory impairment is one of the common symptoms of Alzheimer’s disease. However, impairment in visuospatial and visuospatial memory function has not been focused on as much as that of episodic memory function. We developed a visuospatial memory test, the Hidden Objects Test (HOT), that was designed for people to go around the living room of a house created by virtual reality (VR) and find hidden objects.MethodThis study group comprised 17 Alzheimer’s disease dementia (ADD), 14 amnestic mild cognitive impairment (aMCI), and 15 normal controls (NC). All participants completed a sandardized neuropsychological battery and magnetic resonance imaging (MRI). Out of 46 participants, 28 received amyloid positron emission tomography (PET). Participants performed a novel visuospatial memory test in a virtual environment using VR headset HTC Vive. Walking trajectory in the virtual environment was tracked with 13Hz sampling rate. Participants’ movement path was basically assessed by the total distance, duration, and mean speed.ResultTotal HOT score and five subtests scores were differed among ADD, aMCI, and NC (p <0.001). We performed walking trajectory pattern mining as well as basic trajectory feature analysis such as total distance, duration, and speed. Total duration was significantly greater in ADD than in NC (p = 0.008). The number of outliers, over 95% of estimated trajectory, was significantly higher in ADD than in NC (p = 0.002). The number of stay points, an index that participants stayed in the same position, were significantly higher in ADD and aMCI patients compared to NC (ADD vs. NC: p = 0.003, aMCI vs. NC: p = 0.019). Walking trajectory analysis suggested that ADD and aMCI patients wandered rather than going straight to the hidden objects.ConclusionOur study showed that HOT total scores differed among ADD, aMCI, and NC groups. In addition, our study provided application of trajectory data mining methods to explore the patterns of ADD and aMCI patients' walking trajectory, which could be applied to detect behavior of the patients in environments equipped with the internet of things such as future smart home or facilities.
Neuropathological Correlations of Alzheimer’s Dementia with Biomarker of Blood‐Brain Barrier Breakdown
Authors: Bolakale‐Rufai Ikeoluwapo Kendra , French Scott , Arias Juan C , Serrano Geidy E , Beach Thomas G , Weinkauf Craig 
Published: December 2023

AbstractBackgroundThe early stage of Alzheimer’s Dementia (AD) development has been linked to the breakdown of the blood‐brain barrier (BBB), which is maintained by pericytes and other cell types. Platelet‐derived growth factor receptor‐β (PDGFRβ) has been identified as a novel biomarker of BBB‐associated capillary pericyte damage. Our study aimed to explore the potential association between PDGFRβ and neuropathological diagnosis of Alzheimer’s Dementia, as well as GFAP levels‐ a widely recognized AD biomarker that is present in both serum and cerebrospinal fluid (CSF).MethodA cohort of 48 subjects in the Arizona Study of Aging and Neurodegenerative Diseases (AZSAND) with serum and CSF samples, obtained at the time of death, were included in this cross‐sectional study. Enzyme‐linked immunosorbent assay (ELISA) was utilized to detect PDGFRβ and GFAP in serum and CSF. Statistical analyses were performed using Spearman’s rank correlation and Mann‐Whitney U test.ResultBaseline characteristics were similar between AD (n = 28) and non‐AD groups(n = 20). There was a significant increase in levels of serum PDGFRβ in AD compared to unmatched non‐AD subjects (Mean: 6348.2pg/ml vs 4730.1pg/ml, p<0.05). In addition, PDGFRβ in both CSF and serum correlated with Glial Fibrillary Acidic Protein (GFAP), a well‐known biomarker associated with AD (Spearman’s 𝝆 = 0.42, P< 0.01, Spearman’s 𝝆 = 0.46, P< 0.01, respectively.)ConclusionPDGFRβ, a putative marker of BBB integrity, is elevated in the serum of individuals with Alzheimer’s Dementia (AD) and is correlated with GFAP levels measured in both serum and cerebrospinal fluid (CSF). While these findings are promising and suggest the potential use of PDGFRβ as a blood‐based biomarker for AD pathophysiology, further studies with larger sample sizes are warranted to validate the potential of PDGFRβ as a biomarker for AD.
Greater age‐related cognitive decline in perceptual discrimination of objects than scenes: A cross‐cultural study
Authors: D'Souza Aminette , Lawrence Andrew D , Alladi Suvarna , Graham Kim S 
Published: December 2023

AbstractBackgroundAccording to the “PMAT” framework, two distinct cortico‐hippocampal networks – the posterior‐medial (PM) and anterior‐temporal (AT) networks – are involved in the processing of scene and object content respectively (Ranganath & Ritchey, 2012). It has been suggested that aging predominantly affects the AT network (Berron et al., 2018), and recent studies show evidence for early impairment in object relative to scene mnemonic discrimination with age (Reagh et al., 2016; Gusten et al., 2021). Age‐dependent impairments in object discrimination even exist outside the realm of episodic memory tasks, such as in perceptual oddity tasks (Graham et al., 2010). We aim to extend these findings with i) a digital Oddity perceptual discrimination task, and ii) a cross‐cultural sample.MethodWe tested healthy participants in the UK (n = 141) and India (n = 149) aged between 18‐70 years on a novel multi‐category Oddity discrimination task including object and scene categories. Using a combined speed‐accuracy measure, Inverse Efficiency Score (IES), we applied a mixed‐effects modelling approach to analyse the age trajectory of performance across categories.ResultsWe found a significant decline in performance with age across stimulus categories and cultures, and object performance showed a significantly steeper decline than scenes in both cultures.ConclusionThese findings are amongst the first to indicate that the Oddity discrimination task is sensitive and specific to age‐related cognitive decline across cultures. Notably, these findings support the idea that the object/ AT network is more sensitive to age (potentially reflecting tau pathology) than the scene/ PM network (Berron et al., 2020). Therefore, perceptual discrimination tasks may be a promising cross‐cultural assessment tool for the early detection and differential diagnosis of patterns of age‐related cognitive decline.
Hippocampal volume as mediator between physical fitness and cognitive performance in old age – preliminary results
Authors: Schwarck Svenja , Vockert Niklas , Müller Patrick , Molloy Eóin N. , Fischer Larissa , Hochkeppler Anne , Schumann‐Werner Beate , Kreißl Michael C. , Kreutz Michael R. , Düzel Emrah , Maass Anne 
Published: December 2023

AbstractBackgroundPrevious studies show that physical activity counteracts age‐related memory decline and is positively associated with hippocampal volume. However, only few studies examined if hippocampal volumes mediate the effect of physical activity on cognitive performance. Furthermore, exercise modalities other than aerobic activity are rarely considered in this context. Since sarcopenia (muscle atrophy) is associated with age‐related cognitive decline, muscular capacity seems to be another essential fitness indicator.MethodForty‐one cognitively unimpaired older adults (age: 72.94 ± 7.85yrs; 24 female) underwent a comprehensive neuropsychological test battery assessing, i.a., global cognitive performance using CERAD‐Plus (Consortium to Establish a Registry for Alzheimer’s Disease) and PACC5 (preclinical Alzheimer’s cognitive composite). Their physical fitness was measured in the form of both aerobic (VO2max) and muscular capacity (z‐normalized composite: grip strength, appendicular skeletal muscle mass and walking performance). Anterior (aHCV), posterior and whole hippocampal volumes (wHCV) were extracted from their T1w MRI images (3T MEMPRAGE, 0.8×0.8×0.8mm resolution) using the T1‐ASHS segmentation algorithm (manual correction of 32 hemispheres). Total gray matter volumes (GMV) were extracted using CAT12 in SPM12. Mediation analyses were performed to test the hypothesis that GMV or hippocampal volumes (corrected for intracranial volumes) mediate the positive effect of physical fitness on cognitive performance including age, sex and education years as covariates (bootstrapping approach: 10000 iterations).ResultHigher aerobic capacity (VO2max) was related to better cognitive performance (CERAD, p = .048), as was higher muscular capacity (CERAD, p = .002; PACC5, p = .002). Higher muscular capacity, but not VO2max, further predicted aHCV (p = .021) and wHCV (p = .035). Only wHCV mediated the relationship between muscular capacity and global cognitive performance (PACC5, p = .045).ConclusionOur results provide further evidence that higher aerobic and muscular capacity are associated with better global cognitive performance in older adults. While preliminary, the results suggest that muscular capacity exerts its neuroprotective effects at least partially via greater structural integrity of the hippocampus. The absence of a mediation effect of GMV may support the specific importance of maintained hippocampal structural integrity against cognitive decline. However, our small sample size may limit the statistical power to detect effects.
Design of Small Fluorescent Probes for Imaging Alzheimer’s Disease Pathology
Authors: Kladnik Jerneja 
Published: December 2023

AbstractBackgroundDespite enormous efforts, early diagnosis of Alzheimer’s disease (AD) remains difficult. To date, there is no reliable diagnostic tool to identify biomarkers in the developing stages of AD [1]. In recent years, our group has focused part of the research on the development of small fluorescent molecules capable of effectively labelling AD biomarkers such as amyloid β plaques and tau protein [2, 3].MethodsWe designed and synthesised a library of small fluorescent molecules that were tested in vitro for their binding affinity (Kd
) and change in optical properties upon binding to amyloid β fibrils. In addition, the most promising molecules were used to perform ex vivo labelling of post‐mortem AD brain tissue examined by fluorescence microscopy.ResultsOur synthesized fluorescent probes consist of three building blocks, i.e., electron‐donating (EDG) and electron‐withdrawing groups (EWG), linked to different unsaturated hydrocarbon (HC) linkers (Figure 1), which enable the so‐called “push‐pull” effect leading to fluorescence. First, we investigated how the individual building blocks affect the spectroscopic properties (absorption, emission, excitation, quantum yield) of the prepared molecules in different solvents, representing a simplified polarity model of the AD biomarker binding sites (Figure 2). Furthermore, the compounds evaluated in vitro bound to amyloid β1‐42 fibrils with submicromolar Kd
values. Moreover, the selected compounds were shown to successfully stain amyloid β plaques as well as tau proteins on AD brain slices (Figure 2).ConclusionBased on the results we conducted structure‐spectroscopic‐affinity relationship study and determined how the building blocks of our fluorescent probes affect the optical as well as affinity properties when bound to amyloid β fibrils. Through in vitro and ex vivo studies, our probes are being systematically tested to identify the best candidate capable of achieving our final goal – the early detection of AD biomarkers in the patient’s blood, which would lead to a generally applicable, minimally invasive, cost‐effective, and long‐term traceable diagnostic assay.1. Hansson, O., et al., Alzheimers. Dement., 2022, 18, 2669‐2686.2. Šarlah, D., et al., Molecules, 2016, 21, 267.3. Rejc, L., et al., J. Med. Chem., 2017, 60,8741‐8757.
Demonstration of the iADRS as an integrated measure of global disease severity in early symptomatic Alzheimer’s disease using Rasch measurement theory (RMT)
Authors: Atkins Alexandra S , Marquis Sarah , Cano Stefan , Delbecque Laure , Ye Wenyu , Wessels Alette M 
Published: December 2023

AbstractBackgroundAs an outcome measure in Alzheimer’s disease (AD) clinical trials, the integrated Alzheimer’s Disease Rating Scale (iADRS) assesses the impact of cognitive loss on the ability to perform daily activities. The iADRS integrates items from the ADAS‐Cog13 and the ADCS‐iADL, providing a measure of global AD severity. The present work evaluated integration of cognitive and functional items within the iADRS using RMT, a psychometric approach that models individual items and responses on to a single measurement continuum representing a latent construct (i.e., disease severity).MethodRMT was performed using RUMM2030 using data from the Phase 2, placebo‐controlled TRAILBLAZER‐ALZ study designed to evaluate the safety and efficacy of donanemab in participants with early symptomatic AD. Data from 245 participants were pooled across treatment arms and timepoints (7 timepoints over 18 months).ResultThe iADRS person separation index (PSI) was 0.89, indicating good reliability and ability to differentiate between levels of impairment. Results also indicated good item‐person targeting, with items covering the range of disease severity (mean = ‐1.27, SE = 0.67). The hierarchy of items along the iADRS measurement continuum (Figure 1) reflected observed patterns of clinical decline. Delayed episodic memory impairments preceded broader impairments in immediate memory and memory‐dependent iADLs, including talking about recent experiences (reading, television); more widespread deficits in iADL functioning (telephone use, meal preparation) emerged next, followed by multi‐domain cognitive impairments in orientation and language. While cognition (specifically memory) was impaired earlier than function, cognitive and functional items demonstrated similar rates of decline along the disease severity continuum.ConclusionModel fit and item placement provide support for integration of cognitive and functional items within the iADRS. Placement of items along a single continuum revealed a mixture of cognitive and functional items sensitive to impairment across the spectrum of mild symptomatic disease, and demonstrated how items work together to provide improved coverage of disease‐related impairments. The findings provide further support for the use of the iADRS in clinical trials as an integrated assessment of global disease progression in early symptomatic AD.
Examination of Genetic Risk Factors for Alzheimer’s Disease in a Cohort of Familial Longevity: the Long Life Family Study
Authors: Xicota Laura , Cheng Rong , Barral Sandra , Honig Lawrence S. , Schupf Nicole , Gu Yian , Cosentino Stephanie , Zmuda Joseph M , Perls Thomas T. , Christensen Kaare , Province Michael A , Lee Joseph H. 
Published: December 2023

AbstractBackgroundGenetic risk factors have been explored extensively for late onset Alzheimer’s Disease (LOAD). The largest meta‐analysis GWAS studies to date (Bellenguez et al., 2022) identified 83 single nucleotide polymorphisms (SNPs) associated with LOAD in the general population. The Long Life Family Study (LLFS) is aimed to identify factors associated with familial longevity and healthy aging by examining US and Danish families. Our earlier studies have shown that LLFS families are at lower risk of several age‐related diseases, including LOAD. Here, we will: (1) compare allele frequencies and effect sizes of the identified meta‐GWAS variants against those in LLFS; and (2) assess whether a polygenic risk score (PRS) based on meta‐GWAS variants differs between LOAD vs. cognitively healthy in LLFS.MethodWe examined LLFS participants who were Non‐Hispanic Whites, had available cognitive and whole genome sequencing (WGS) (n = 4,220). Allele frequencies were estimated based on founders only. Association analyses were performed via logistic regression using Wald test and adjusting for sex, age, site, education, first principal components, and the genetic relationship matrix. PRS was calculated using a weighted formula, and to account for family structure, means for each status per family were obtained.ResultIndependent of LOAD status, 13 SNPs had significantly different allele frequencies between the two studies. Minor allele frequencies of 10 of the SNPs were lower in LLFS when compared with Bellenguez et al. When examining the relations between LOAD and the 77 available SNPs, only five variants appeared to be associated in LLFS. The direction of association differed for two of the SNPs. Lastly, estimated PRS scores did not differ by LOAD status (affected vs unaffected: ‐0.059 vs. ‐0.054, respectively).ConclusionHere we show that variants associated with LOAD in the general population were not necessarily associated with LOAD in in the LLFS cohort, a cohort ascertained for familial healthy aging. When estimating disease risk using genetic markers, as expected, ascertainment needs to be taken into consideration.