bluuebunny/crossref_metadata_2025_split huggingface dataset:
Characteristics of β‐secretase activity on APP‐V604M and APP‐V669L
Authors: Kim Danyeong , Shim Kyu Hwan , Bagyinszky Eva , Van Vo Giau , Kang Min Ju , Senanarong Vorapun , Limwongse Chanin , Shin Seunghwan , Jeong SoonPyo , Kim Jongsung , Park Young Ho , Youn Young Chul , Kim SangYun , An Seong Soo 
Published: December 2022

AbstractBackgroundSeveral mutations near the amyloid‐beta peptide (Aβ) of Amyloid Precursor Protein (APP) were reported to as pathogenic mutations in Alzheimer's disease (AD), especially in early‐onset Alzheimer's disease (EOAD). β‐Secretase would cleave APP and release sAPPβ and CTF99. Then, γ‐secretase would cleave CTF99 sequentially in generating Aβ. Previously, APP‐V604M and APP‐V669L mutations (APP Seoul mutation) were found from patients with EOAD and their mutant cell lines were established by CRISPR/Cas9. Their pathogenicity of APP‐V604M was demonstrated the mutant cells from observing the increased both of Aβ42/40 ratio and oligomers. For APP‐V669L, the decreased ratio Aβ42/40 was noticeable from the elevation of Aβ40. Still, increased Aβ oligomers were measured. Here, their pathogenicity was supported by measuring β‐secretase activity in above mutant cells.MethodPreviously, APP‐V604M and APP‐V669L cells were generated by CRISPR/Cas9. Cells were seeded and incubated for 48 h. After washing, conditioned media was added and incubated for 48 h. Afterwards, cytosolic proteins and solubilized membrane were extracted with the commercial kit. β‐secretase activities were measured with the substrate at ex/em 355/510 nm.ResultDifferences of β‐secretase activity were observed from above mutations in comparison with control. From the cytosolic protein fractions, the increased β‐secretase activity was observed from APP‐V604M, whereas the decreased activity was monitored from APP‐V669L. Interestingly, from the solubilized membrane fractions, the higher β‐secretase activities were seen than cytosolic protein tractions. The similar activities were measured between APP‐V604M and the control, whereas the decreased β‐secretase activities were measured in APP‐V669L than the control.ConclusionSince APP mutations would directly affect by β‐secretase in generating Aβ, it was important to monitor the β‐secretase activity for supporting the mutant. Here, differences in β‐secretase activities were quantified in APP‐V604M and APP‐V669L mutant cells. As APP Seoul mutation was located at the β‐secretase cleavage site, it would be detrimental to β‐secretase activity. Increased activity on APP‐V604M suggested the possible alteration of structural/cleavage β‐secretase activity from outside of Aβ region. Moreover, the higher β‐secretase activity was observed in the fraction from membrane than the cytosolic fraction. Our results emphasize the importance of measuring β‐secretase activity from the membrane fraction.
Aβ1‐42‐related sodium‐calcium exchanger isoform‐3 downregulation in models of Alzheimer’s disease: Therapeutic significance of Withania somnifera roots extract
Authors: Afewerky Henok Kessete , Li Hao , Zhang Tongmei , Li Xinyan , Mahaman Yacoubou Abdoul Razak , Duan Limin , Qin Pengwei , Zheng Jiequn , Pei Lei , Lu Youming 
Published: December 2022

AbstractBackgroundNa+‐Ca2+ exchanger isoform‐3 (NCX3) take‐parts in the aberrant Ca2+‐influx seen during neuronal excitotoxicity. However, the NCX3‐Aβ1‐42‐associated cytotoxicity and whether renovation of the aggregated Aβ1‐42‐induced NCX3 downregulation prevents or delays the onset of Alzheimer’s disease (AD) and AD‐related pathology remain unclear. Withania somnifera (W. somnifera), an indigenous traditional medicinal plant, has a long history of uses in preventing aging‐related neurological‐health impairments. However, this plant’s roots extract therapeutic value in neurodegenerative diseases, such as AD, albeit far less well studied.MethodsMicroscopic fluorescence and haemocytometer cell viability counting were performed to examine contributions of NCX3 against Aβ1‐42‐induced cytotoxicity in BHK‐cells. Authenticated W. somnifera‐dried‐roots were powdered, and the powder’s methanolic extract was used for phytochemical screening of the roots‐bioactive constituents and the 5×FAD mice gavage treatments from postnatal day 30 (P30) to P60 while maintaining their daily bodyweight records. After treatments, in vivo‐cognitional studies and then neurochemical‐examinations of the NCX3 immunoblot expression level, a sandwich ELISA and microscopy of Aβ plaque deposition, and antioxidant activity assays were performed in the AD‐associated brain regions at the mice age of 4 months.ResultsThe cell‐based studies revealed positive roles of NCX3 in the resistance against Aβ1‐42 exposure toxicological damages. Phytochemical screening of the extract attested presence of antioxidants as major bioactive constituents of the roots. The mice recorded bodyweights during treatments statistical‐analysis evidenced that the extract has no potential toxicity. The cognitional studies data indicates that the treatment group mice showed significant improvements than vehicles (p<0.01). Interestingly, subsequent studies in the mice’s cortex‐ and hippocampus‐homogenates showed that the W. somnifera prevents NCX3 suppression, significantly reduces Aβ1‐42 expression, and normalizes oxidative stress. Moreover, confocal microscope immunoreactive studies indicated reduced depositions and distributions of Aβ plaques in the treatment group AD‐associated brain tissues.ConclusionThese findings suggest the relevance of NCX3 against effects of Aβ1‐42‐associated cytotoxicity and that the W. somnifera antioxidant constituent’s bioactivity with no indications of toxicity, operating against Aβ‐induced NCX3 downregulation, may have a therapeutic role for augmenting NCX3 physiological properties in the maintenance of ionic Ca2+ homeostasis and ameliorates cognition in the 5×FAD mouse‐model, and therefore, might be valuable in AD‐pharmacological medicine.
PART is part of SNAP‐MCI
Authors: Wisse Laura EM , Xie Long , Lyu Xueying , Das Sandhitsu R. , de Flores Robin , Lane Jacqueline , Yushkevich Paul A. , Wolk David A. , Initiative Disease Neuroimaging 
Published: December 2022

AbstractBackgroundMild Cognitive Impairment with Suspected non‐Alzheimer’s Pathophysiology (SNAP‐MCI) represents a group of patients with Alzheimer’s disease (AD) like neurodegeneration without beta‐amyloid pathology. While this group likely has a heterogeneous etiology, tau pathology, as in Primary Age‐Related Tauopathy (PART), has been hypothesized to play a major role. We investigate tau positron emission tomography (PET) uptake in the medial temporal lobe (MTL) in SNAP‐MCI and the association of MTL Tau‐PET uptake with structural measures and delayed recall in beta‐amyloid negative (A‐) MCI patients.Method237 MCI patients and 301 A‐ controls with available beta‐amyloid and tau PET and magnetic resonance images (within 200 days) were included. Baseline hippocampal volume and entorhinal cortex (ERC) and Brodmann areas (BA)35 thickness were obtained using an in‐house developed pipeline and annualized atrophy rates were estimated in an unbiased fashion using follow‐up MRIs within 4.5 years. Βeta‐amyloid status (A+/‐) was determined by a standard cut‐off (Florbetapir: 1.11; Florbetaben: 1.08) and neurodegeneration status (N+/‐) by hippocampal volumes, corrected for intracranial volume, using the 90th percentile of A+ AD patients as the cut‐off. Tau‐PET standardized uptake value ratio (SUVR) in the ERC/BA35 was calculated. A composite z‐score of delayed recall at baseline and change over 2 years was obtained.ResultSNAP‐MCI had significantly higher ERC/BA35 Tau‐PET SUVR than A‐ controls (Table 1, corrected for age) and qualitatively higher than A‐N‐ MCI (p=0.10). ERC/BA35 Tau‐PET SUVR in A‐N‐ MCI was not significantly different from A‐ controls.In A‐ MCI patients, ERC/BA35 Tau‐PET SUVR was significantly associated with BA35 thickness and hippocampal, ERC and BA35 atrophy rates, corrected for beta‐amyloid PET SUVR (Table 2; Figure 1). MTL structural measures, but not ERC/BA35 Tau‐PET SUVR, were associated with cross‐sectional and longitudinal delayed recall measures (Table 3; Figure 2).ConclusionSNAP‐MCI had elevated ERC/BA35 Tau‐PET SUVR and ERC/BA35 Tau‐PET SUVR was associated with MTL structural measures in A‐ MCI patients. This indicates that tau pathology might be an important driver of neurodegeneration in the absence of beta‐amyloid pathology, supporting the notion that PART contributes to SNAP‐MCI. Additionally, MTL structure was associated with memory performance, consistent with SNAP not being a benign condition.
CSF‐plasma biomarker profiles from BioFINDER MCI patients using the same technology
Authors: Vanmechelen Eugeen , Dewit Nele , Vanbrabant Jeroen , Mauroo Kimberley , Stoops Erik , Stomrud Erik , Janelidze Shorena , Hansson Oskar 
Published: December 2022

AbstractBackgroundTechnological advancements have made it possible to translate changes in cerebrospinal fluid (CSF) into promising plasma biomarkers, such as the amyloid β ratio (Aβ42/Aβ40) and phosphorylated tau (p‐tau), but comparing CSF and plasma levels were often based on different technologies. Combining biomarkers have demonstrated a superior performance of the ratio of p‐tau over Aβ42 to discriminate Aβ‐positive (Aβ+) and Aβ‐negative (Aβ‐) groups in CSF, especially using automated immunoassay platforms, but has not yet been studied in plasma.MethodIn a subset of 155 MCI individuals of the BioFINDER‐1 study, from which 84 paired CSF‐plasma were available for analysis, Aβ42, Aβ40 and p‐tau181 were determined using ADx Simoa assays (Thijssen et al, 2021; Bayoumy et al, 2021) in both fluids using the appropriate dilution factors.ResultThe intra‐run %CV was between 1.7 and 2.6% for both Aβ markers in CSF and plasma and was higher in plasma for p‐tau181 than in CSF with respectively 10.5 and 1.7%. Both CSF Aβ42, Aβ40 and Aβ42/Aβ40 were highly correlated to CSF Aβ measurements using the MSD platform: spearman ρ of 0.845; 0.828; and 0.882 for respectively for Aβ42, Aβ40 and their ratio. In the paired CSF‐plasma analysis the strongest correlation was found for p‐tau181/Aβ42 and p‐tau181 with respectively a ρ=0.689 and 0.616 and a significantly weaker correlation for Aβ42/Aβ40 ratio (ρ=0.283). Defining an Aβ+ and an Aβ‐ subgroup by using a previously verified CSF Aβ42/Aβ40 of 0.07, all plasma biomarkers could differentiate Aβ+ and Aβ‐ individuals. The highest AUC was observed for p‐tau181/ Aβ42, 0.806, significantly (p=0.0465) higher than p‐tau181 (0.784) and the Aβ42/Aβ40 (0.688)(Fig 1).ConclusionCorrelations in paired CSF‐plasma samples using the same technology are significant, but weak for some of them suggesting a different turnover of these analytes in these fluids. Nevertheless combining both well‐established pathological markers in plasma, p‐tau and Aβ42, may be a simple way to enhance early diagnosis based especially if automated immunoassay platforms are envisaged.
African American experience of FTD: A sub‐cohort assessment of the FTD Insights Survey
Authors: Dodge Shana G. , Vincent Lakecia , Dacks Penny A. , Wheaton Dianna K.H. 
Published: December 2022

AbstractBackgroundWhile efforts are underway to better understand the prevalence, incidence, pathophysiology, and phenomenology of FTD, most research participation has been dominated by persons of European descent. Better understanding of early signs, the diagnostic journey, and the functional impacts in historically underrepresented groups may help shed light on healthcare inequities, support the development of more inclusive research study design, and lay the foundation for more targeted care and interventions.MethodIn preparation for an Externally Led Patient‐Focused Drug Development (PFDD) meeting, the Association for Frontotemporal Degeneration (AFTD) and the FTD Disorders Registry (FTDDR) collaborated to develop the FTD Insights Survey. The online survey queried aspects of the lived experience of FTD from the patient/family/carer perspective.ResultOf the 1,796 respondents that completed the survey, twenty‐five represented the experience of African American persons diagnosed with FTD from the perspective of those diagnosed (n = 4) and care partners (n = 21). Two additional respondents reported on their experience as African American biological family members of those with FTD. Thirty‐six percent of African Americans needed to see 4 or more doctors before receiving an FTD diagnosis, compared to 18% of total respondents, and were more likely to initially receive a different diagnosis (80% vs. 45%). While patterns of the first symptoms were reported similarly across all participants, African Americans were more likely to report having initially experienced changes in thinking, spatial reasoning, or delusions/hallucinations. African Americans were also more likely to report distress related to language, sleep, and delusions/hallucinations and less likely to report no distress or distress related to cognitive symptoms. African American participants were more likely to endorse wanting a treatment to maintain independence and hold a job than overall participants.ConclusionThe African American perspectives reported on the FTD Insights Survey represent a small sample size of individuals with greater than average levels of education (76% had an Associate’s degree or higher). The experience they report overlaps with those of other respondents, but with key differences including more difficulty in access to timely diagnosis. More information is needed on the lived experience of FTD across people of different cultural, social, economic backgrounds.
User Experience and Compliance Rates of Remote Monitoring Technologies in Alzheimer’s Disease: Preliminary Results of the RADAR‐AD Study
Authors: Muurling Marijn , Hinds Chris , Wu Yuhao , Curcic Jelena , Doherty Aiden , Conde Pauline , Owens Andrew P , de Boer Casper , Aarsland Dag , Narayan Vaibhav A , Visser Pieter Jelle ,   the RADAR‐AD consortium
Published: December 2022

AbstractBackgroundUnlike traditional pen‐and‐paper clinical assessments, remote monitoring technologies (RMTs) can assess participants’ function continuously and objectively during activities of daily living. Despite the potential of RMTs to assess function or assist early disease detection, there is skepticism that age or impairment may render participants unable or unwilling to comply with complex RMT protocols. The 8‐week RADAR‐AD study protocol asks Alzheimer’s disease (AD) patients in all disease stages to wear, amongst others, two activity trackers (Axivity, Fitbit), a wearable camera (Autographer), and use an active smartphone app (Mezurio), with a daily schedule totaling over 400 separate tasks and a parallel schedule for caregivers. This abstract presents preliminary compliance data and participant feedback.MethodWe included amyloid negative control participants (n=47) and amyloid positive preclinical (n=16), prodromal (n=19) and mild‐to‐moderate (n=16) AD participants (Table 1), based on MMSE and CDR scores, in 8 European countries. Metrics based on device data were calculated for participant commitment (study duration completion percentage or wear time) and compliance (task completion percentage). Patient experiences were monitored using bi‐weekly semi‐structured phone interviews.ResultMezurio average commitment and compliance were 90% and 85% respectively (Table 2) and were comparable across diagnostic groups. Wear time of Axivity, Fitbit and wearable camera was high (>86%), with 48% of those offered adopting the optional wearable camera (Table 2). Participant feedback was positive, with relatively few problems reported (Figure 1).ConclusionRADAR‐AD shows that age and impairment are not necessarily barriers to successful deployment of complex RMT study protocols. We acknowledge that our high commitment and compliance rates benefitted from an active rapport between researchers, participants and care givers, which may not be reproducible in every scenario. Nevertheless, this study shows that AD patients are able and willing to comply and engage with technology.This work has received support from the EU/EFPIA Innovative Medicines Initiative Joint Undertaking (grant No 806999). www.imi.europa.eu. This communication reflects the views of the RADAR‐AD consortium and neither IMI nor the European Union and EFPIA are liable for any use that may be made of the information contained herein.
GCase activity and long‐term risk of dementia in Parkinson’s disease
Authors: Oftedal Linn , Dalen Ingvild , Tysnes Ole‐Bjørn , Pedersen Kenn Freddy , Alves Guido , Maple‐Grødem Jodi , Lange Johannes 
Published: December 2022

AbstractBackgroundClinically, patients with Parkinson disease (PD) carrying a mutation in the glucocerebrosidase (GCase) gene (GBA) are at higher risk of dementia, suggesting that GCase dysfunction may contribute to a more severe disease course, although evidence is lacking. We aimed to discover if cerebrospinal fluid (CSF) GCase activity is altered in newly diagnosed PD patients and if GCase activity at diagnosis predicts the future development of dementia.MethodWe measured CSF GCase activity in 117 PD patients from the Norwegian ParkWest study, a population‐based study of incident PD with 10 years of biannual, prospective follow up, and 50 control subjects without neurological disease. PD dementia diagnosis was set according to established clinical criteria. Parametric accelerated failure time models were applied to analyze the association of GCase activity at the time of PD diagnosis with dementia free survival.ResultGCase activity was reduced in PD patients with (0.92±0.40 mU/mg) or without GBA mutations (1.00±0.37 mU/mg) compared to controls (1.20±0.35 mU/mg). GCase activity at the time of diagnosis was lower in PD patients who developed dementia within 10 years (n=41, 35%) than in those who remained free of dementia (p = 0.001). Further, patients in the lowest tertile of GCase activity at PD diagnosis were at 3‐fold increased risk of developing dementia in the next ten years (HR 3.10; 95% 0.72 to 4.68; P= .014; Figure), a finding that was also independent of GBA carrier status.ConclusionThis is the first study to show both that GCase dysfunction is evident in idiopathic PD at the time of diagnosis and that low GCase activity is associated with greater risk of developing dementia over the next ten years. GCase‐targeting compounds are among the most promising strategies towards disease‐modifying treatments in PD, and evidence for the association of CSF GCase activity with disease progression, independent of GBA mutation status, will have important implications for clinical trial design and patient management.
A Role for Epigenetic Mechanisms in the Lewy Body Dementias
Authors: Imm Jennifer L , Harvey Joshua , Creese Byron , Chouliaras Leonidas , Dempster Emma , Ballard Clive G , O'Brien John T , Aarsland Dag , Mill Jonathan , Pishva Ehsan , Lunnon Katie 
Published: December 2022

AbstractBackgroundThe Lewy body diseases, Dementia with Lewy bodies (DLB), Parkinson’s disease (PD) and Parkinson’s disease dementia (PDD) are all neurodegenerative diseases classified by the accumulation of alpha‐synuclein in neurons, forming Lewy bodies (LB). We hypothesise that these LBs cause epigenetic changes within neurons and surrounding cells and that these changes can be used to distinguish the different diseases from one another.MethodBulk tissue from the cingulate gyrus and prefrontal cortex was analyzed on the Illumina Infinium Methylation EPIC array generating a quantitative measure of DNA methylation for over 850,000 CpG sites (n=∼100/disease group). Linear regression and pathway analyses were then used to identify loci that are significantly different or specific to each disease.ResultStudy groups have been sourced consisting of cases with PD, PDD and DLB based on LB deposition and clinical symptom staging. Age‐matched control cases have been selected that have similar levels of concomitant AD pathology to the disease groups. We have identified significant changes in methylation associated with both phenotype and neuropathology alongside the cellular pathways these changes correspond with.ConclusionWe have collated a well powered study cohort to interrogate the epigenetic basis of neuropathological progression and clinical staging of LB disease, controlling for levels of concomitant AD pathology. We have completed DNA methylation analysis for two disease relevant brain regions and identified both phenotype neuropathology associated changes within these regions. Processing of samples for fluorescence activated nuclei sorting (FANS) and laser capture microdissection (LCM) has begun (n=15/group) to assess the cell type specificity of the methylation changes and the effect of Lewy bodies on neuronal methylation respectively.
Diffusion MRI subnetwork efficiency is associated with cognitive resilience to AD pathology in cognitively unimpaired older adults at risk of AD dementia
Authors: Qiu Ting , Liu Zhen‐Qi , Strikwerda‐Brown Cherie , St‐Onge Frederic , Binette Alexa Pichet , Descoteaux Maxime , Villeneuve Sylvia ,   the PREVENT‐AD Research Group
Published: December 2022

AbstractBackgroundWhile higher levels of Aβ and tau pathology are typically associated with more pronounced cognitive decline in Alzheimer’s disease (AD), some older adults exhibit normal cognition even with a substantial burden of AD pathology. This phenomenon is known as ‘cognitive resilience’. The potential role of structural connectivity in cognitive resilience remains inconclusive. The present study tested whether higher global efficiency in structural brain networks moderate the relationship between AD pathology and cognitive performance in the preclinical phase of AD.MethodWe studied 118 cognitively normal older adults from the family history enriched Prevent‐AD cohort. Diffusion‐weighted MRI was used to measure the structural connectome, PET to measure global Aβ (18F‐NAV4694) and entorhinal tau (18F‐Flortaucipir) pathology, and the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) to evaluate cognitive performance. We first used graph theory analyses to calculate global efficiency of networks known to be affected in early AD (i.e., limbic and default mode network (DMN)). Then multiple linear regressions were performed to examine relationships between Aβ / tau pathology, cognitive performance, and global efficiency of the two subnetworks. Interaction analyses were used to examine whether network efficiency attenuates the relationships between AD pathology and cognitive performance.ResultAs expected, higher levels of Aβ and tau pathology in the brain were associated with worse cognitive performance in individuals at risk of AD (Figure 1). Higher entorhinal tau pathology was also associated with lower global efficiency in the limbic network (Figure 2). Subsequent interaction analyses showed that global efficiency in the limbic moderated the relationships between AD pathology and cognitive performance. Specifically, higher global efficiency was associated with an attenuated effect of both amyloid and tau pathology on delayed memory performance (Figure 3).ConclusionIndividuals with higher global efficiency in the limbic structural network exhibit better memory performance at a given level of AD pathology in preclinical stages of the disease. Structural network properties of the brain may play an important role in maintaining cognitive performance in the face of AD pathology, and could serve as a potential biomarker for cognitive resilience.