bluuebunny/crossref_metadata_2025_split huggingface dataset:
Initial clinical scans using [18F]ACI‐12589, a novel α‐synuclein PET‐tracer
Authors: Smith Ruben , Capotosti Francesca , Schain Martin , Ohlsson Tomas , Touilloux Tanja , Hliva Valerie , Vokali Efthymia , Luthi‐Carter Ruth , Molette Jerome , Dimitrakopoulos Ioannis K , Jögi Jonas , Stomrud Erik , Hall Sara , Bratteby Klas , Tampio Elina , Pfeifer Andrea , Kosco‐Vilbois Marie , Streffer Johannes , Hansson Oskar 
Published: December 2022

AbstractBackgroundTo study the ability of the newly developed α‐synuclein Positron Emission Tomography (PET) tracer, [18F]ACI‐12589, created and developed by AC Immune SA, to detect α‐synuclein neuropathology in vivo, in clinically diagnosed patients with α‐synucleinopathies.MethodWe intend to scan a total of up to 50 participants with different diseases associated with α‐synuclein and age‐ and gender‐matched controls. These will include participants with Parkinson’s disease (PD), Multiple System Atrophy (MSA), Dementia with Lewy bodies (DLB), or Parkinson’s disease caused by a duplication in the α‐synuclein gene, in addition to neurologically healthy volunteers. At the time of abstract submission, 23 participants have undergone [18F]ACI‐12589 PET scans. 20 scans consist of 0‐90 min dynamic scans with arterial blood sampling for blood input activity and metabolite analysis, two are full dynamic scans and one a 60‐90 min static scan without blood sampling. In addition, participants have undergone structural MRI, DaTscan or [18F]DOPA PET, and cognitive and motor testing (UPDRS‐III).ResultThe data are currently being processed and analyzed. Initial image analyses suggest that there is ACI‐12589 retention in brain areas affected by the disease process (such as the basal ganglia and cerebellar white matter) in participants with MSA, but also a potential age‐dependent retention in the basal ganglia and brain stem of controls.ConclusionWe will be presenting initial promising clinical data on the novel α‐synuclein PET tracer [18F]ACI‐12589, the initial analysis of which suggests tracer binding consistent with expected patterns of α‐synuclein pathology based on clinical manifestations. Further analyses are ongoing and our updated findings will be presented at the conference.
Smoking behavior, sleep quality, and physical activity level are associated with cerebral amyloid pathology in non‐demented persons: The Amyloid Biomarker Study
Authors: Oomens Julie Elisabeth , Jansen Willemijn J. , Janssen Olin , Maserejian Nancy Nairi , Verhey Frans R.J. , Vos Stephanie J. B. , Visser Pieter Jelle ,   the Amyloid Biomarker Study Group
Published: December 2022

AbstractBackgroundThe relationship between lifestyle factors and Alzheimer’s disease pathophysiology is not well understood. The aim of this study was to assess the cross‐sectional association between lifestyle factors and amyloid abnormality in individuals with normal cognition (NC) and mild cognitive impairment (MCI).MethodWe selected 39 cohorts from the Amyloid Biomarker Study. Self‐reported lifestyle data were available for 8924 participants with NC and 2403 participants with MCI. Amyloid abnormality was determined with amyloid‐PET (center‐specific cutoffs) or with aß42 level in CSF (data‐driven or center‐specific cutoffs). Lifestyle data was harmonized across cohorts and dichotomized into ever smoked yes/no, current alcohol consumption yes/no, currently physically active yes/no and current sleep problems yes/no. Education was dichotomized into ‘high’ or ‘low’ at the median of 16 years. Generalized estimating equations with amyloid abnormality as outcome and single lifestyle factors as predictors were used. Interactions with age, sex, education, cognitive status and APOE‐e4 carrier status were assessed and these variables were added as covariates to all models.ResultThirty‐one percent of participants were amyloid positive, 37% were ApoE‐4 carrier, and 55% were female. The mean age was 68.7 (SD8.7). Twenty‐five percent of participants smoked, 54% consumed alcohol, 30% experienced sleep problems and 25% were physically inactive. Overall, smoking was associated with a slightly increased prevalence of amyloid abnormality (2%; p = 0.03). In NC, sleep problems were unrelated to the prevalence of amyloid abnormality while in MCI, sleep problems were associated with a lower prevalence (15.3%; p<0.001). Physical activity was related to higher prevalence of amyloid abnormality in APOE‐e4 carriers (5.9%; p<0.001) while this association was not found in noncarriers. Age, sex and educational level did not modify the identified associations between lifestyle factors and amyloid abnormality. Alcohol consumption was unrelated to amyloid abnormality.ConclusionSmoking behavior, sleep quality, and physical activity were associated with amyloid abnormality depending on cognitive and APOE‐e4 status. A better understanding of the associations between lifestyle factors and cerebral amyloid pathology in different subgroups will aid in identifying those at risk and contribute to the development of targeted intervention strategies.
Molecular docking study and ADMET prediction of phytoconstituents of Withania Somniferra Flem. in Alzheimer’s disease: an insilico explorative study
Authors: Medhi Bikash , Prajapat Manisha ,   Insilico‐Study
Published: December 2022

AbstractBackground
Withania somniferra Flem. (brahmi) is known for its neuroprotective property and protective action against AD. Among different phytochemicals of WS, which phytoconstituents is responsible for this neuroprotection in AD is unknown.MethodProtein Preparation, Ligand Preparation, Molecular Docking on PDB structure of target proteins GSK‐3 beta, CDK‐5, NMDA,SORLA/SORL1,P2×7R, beta catenin, sTLR5 from protein data bank were performed using Schrodinger maestro 12Ligand preparation: Compound was retrieved from pubchem Withaferin‐A and withanolide‐A.Molecular Docking: All in silico calculations and procedures were carried out using Schrödinger software Maestro suite 2019, on an Acer predator laptop with an operating system consisting Linux Ubuntu OS 18.04.02 LTS platform.Pharmacokinetics properties of ligands: admetSAR server (http://lmmd.ecust.edu.cn:8000/) (19), AMDETlabs server (admet.scbdd.com/) and SwissADME server (www.swissadme.ch/) (21) were used for evaluation of pharmacokinetic properties of the ligands (absorption, distribution, metabolism, excretion and toxicity).ResultOut of these 30 ligands, Withaferin‐A (binding energy to the inhibitory domain of gsk3 beta and beta catenin is ‐5.135, ‐7.764 respectively and withanolide‐A binding energy to the inhibitory domain of gsk3 beta and beta catenin is ‐4.371, ‐6.946 and Both the ligands showed good binding profile, favorable pharmacokinetic profile, no violation of drug ability rules. Both the ligands showed permeability through blood brain barrier. Both the ligands shown non Ames toxicity, non carcinogen and weak inhibitor of HERG. Phytochemical of WS (Withaferin‐A and withanolide‐A) showed good binding profile against gsk3beta targets in AD.ConclusionPhytochemical of WS (Withaferin‐A and withanolide‐A) showed good binding profile against Gsk3beta AND Beta catenin targets in AD. We need further studies to evaluate individual efficacy of these phytochemicals in different settings (in‐vitro and in‐vivo).
Letters of Intent for Pilot Projects Affirm the Heterogeneity of Dementia Family Caregiving
Authors: Hepburn Kenneth , Waldrop Drenna , Song Mi‐Kyung , Clevenger Carolyn K , Aflatoony Leila , Higgins Melinda , Glover Crystal M , Lindauer Allison , Perkins Molly 
Published: December 2022

AbstractBackgroundThe Emory Roybal Center for Dementia Caregiving Mastery (P30AG064200) supports pilot intervention projects designed to enhance informal caregiving mastery and seeks to further their development, following the NIH Stage Model. The Center’s core assertions are that dementia caregiving is heterogeneous in nature and that caregiving role demands are positioned within a variety of intersections involving dementia stage and type, the nature of care tasks, caregiver‐care recipient relationships, and/or other social determinants including race/ethnicity, culture, class, and geography. Thus, interventions to develop/enhance caregiving mastery must be designed within the context of these intersections. This presentation demonstrates the resonance of the Center’s central theme and illustrates the wide range of caregiving situations/contexts investigators seek to address.MethodWe analyzed the letters of intent (LOI) investigators submitted to the Center In its three years of operation. The LOIs describe context/situation‐specific caregiving mastery interventions investigators seek to develop.ResultIn three years, the Center received 67 LOIs from investigators in 26 U.S. states. Most (85%) were from female investigators; the majority were from early‐stage (Assistant Professor) investigators (52%) and investigators from underrepresented groups (54%). Responses came from 10 different disciplines (including Behavioral Sciences (including Social Work), 14; Nursing, 12; and Medicine, 10). Proposed interventions fell into three broad (sometimes intersecting) categories: specific caregiving populations (e.g., racial/ethnic groups; specific caregiving relationships); specific caregiving challenges (e.g., skilled care tasks, managing delirium or chronic pain, caregiver self‐care); and dementia types (e.g., MCI, Lewy Body Disease (LBD), and Frontotemporal Dementia). To date, the Center has provided support for pilot projects aiming to enhance mastery in caregivers of persons with Primary Progressive Aphasia and with LBD and couples living with MCI, among Native American caregivers and those from the LGBTQ community and rural caregivers, and those faced with skilled care tasks and who needed to develop skills through distance means.ConclusionThe Center has supported pilot projects that illustrate the importance of appreciating the heterogeneity of dementia caregiving. The voluminous response to the LOI call demonstrates the salience of the heterogeneity theme and underscores the need for additional work to enhance dementia caregiving mastery in its many contexts.
CSF tau phosphorylation at sites 217 and 181 are associated with preclinical and biphasic alterations in resting‐state functional connectivity in Autosomal Dominant AD
Authors: Meeker Karin L. , Barthélemy Nicolas R. , Gordon Brian A. , McDade Eric , Karch Celeste M. , Fagan Anne M. , Strain Jeremy F. , Luckett Patrick H , Benzinger Tammie L.S. , Bateman Randall J. , Holtzman David M. , Ances Beau M ,   the Dominantly Inherited Alzheimer Network (DIAN)
Published: December 2022

AbstractBackgroundIn autosomal dominant AD (ADAD), elevated cerebrospinal fluid (CSF) soluble phosphorylated tau (pT181) increases shortly after amyloid positron emission tomography. Recent advancements have identified additional phosphorylated tau sites, such as phosphorylated tau 217 and 205 (pT217 and pT205), which are associated with amyloid deposition and neuronal dysfunction, respectively. Degradation of cortical brain network resting‐state functional connectivity (RS‐FC) is typically observed at the onset of cognitive impairment and is most prevalent in regions where amyloid and tau accumulate. However, it is unknown how specific phosphorylated tau sites are associated with alterations in brain networks and contribute to the transition from asymptomatic to symptomatic AD.MethodCSF tau phosphorylation occupancy on 217, 181 and 205 residues and RS‐FC were measured in 93 individuals from the Dominantly Inherited Alzheimer Network (amyloid‐negative asymptomatic mutation carrier [(aMCA‐); n=26]; amyloid‐positive asymptomatic mutation carriers [a(MCA+); n=36]; and amyloid‐positive symptomatic mutation carriers [(sMCA+); n=31]). Regression models were used to determine within‐group associations between CSF phosphorylated tau sites and within‐network RS‐FC measures.ResultP‐tau associated RS‐FC alterations began during preclinical stages and continuously changed throughout disease progression. Specifically, within aMCA‐, pT217, pT181, and pT205 were associated with decreased RS‐FC in salience and ventral attention networks, while in aMCA+, pT217 and pT181 were associated with increased RS‐FC in the fronto‐parietal network. In sMCSA+ elevated p‐tau sites were associated with decreased RS‐FC in the cingulo‐opercular, dorsal attention, default mode, and memory networks.ConclusionElevated phosphorylation at specific tau sites is associated with a biphasic pattern of RS‐FC which begins during asymptomatic stages. P‐tau‐ associated RS‐FC alterations were consistent with proposed models of cascading network failure and AD pathophysiology. These results suggest that in ADAD, phosphorylation of tau is associated with widespread and dynamic RS‐FC alterations which begin before the transition to symptomatic AD.
Default Mode Network failure is associated with increased tau PET uptake
Authors: Scott David , Bracoud Luc , Adamczuk Katarzyna , Ingalhalikar Madhura , Conklin Chris , Rousset Olivier , Suhy Joyce 
Published: December 2022

AbstractBackgroundThe accumulation of neurofibrillary tangles contributes to a neurodegenerative cascade toward Alzheimer’s disease. Focal tau deposition may impair signal integrity within a broader network of functionally connected brain regions. 18F‐Flortaucipir PET allows visualization of tau pathology in vivo, and functional compensation between Default Mode Network (DMN) subsystems is an fMRI‐based biomarker of network failure. We sought to characterize the relationship between network failure in the DMN and tau burden throughout the brain.Method620 ADNI3 subject visits with concurrent fMRI and flortaucipir PET scans were selected from the database (http://adni.loni.ucla.edu) for analysis. ADNI PET core PVC values referencing inferior cerebellar cortex were used to index SUVR across the entire FreeSurfer parcellation, and the ADNI MRI core Network Failure Quotient (NFQ) was used as a summary metric of fMRI connectivity strength in the DMN. Linear partial correlation coefficients were calculated for NFQ and SUVR in each brain region, controlling for age. Lasso logistic regression also returned penalized maximum‐likelihood fitted coefficients for a generalized linear model estimating NFQ from regional SUVR; regions with non‐zero coefficients in the sparsest model were included in a composite. A subset of 131 subjects with paired visits at one year follow‐up were included in longitudinal analysis.ResultA significant age‐corrected association was observed between higher NFQ, reflecting worsening DMN failure, and higher flortaucipir SUVR in Braak 1 (p < 0.02) and meta‐temporal composite ROIs (p < 0.03). Age‐corrected partial correlations achieved marginal significance (p < 0.05) in bilateral entorhinal, inferior and middle temporal, superior parietal and caudal middle frontal cortices, left posterior cingulate and right isthmus cingulate. Lasso regression revealed a subset of non‐zero coefficients including frontal, temporal, cingulate and subcortical brain regions. In the longitudinal analysis, age‐corrected baseline tau load in Braak 5/6 and a set of frontoparietal subregions was marginally significantly associated with change in NFQ after 1 year.ConclusionFunctional network failure in the DMN is associated with greater tau burden inside and outside the network. These results suggest the NFQ is a viable fMRI‐based biomarker for tau pathophysiology and disease state.
Gantenerumab treatment increases plasma beta‐amyloid(1–42) and decreases plasma pTau
Authors: Bittner Tobias , Scelsi Marzia A. , Kollmorgen Gwendlyn , Jethwa Alexander , Kerchner Geoffrey A. , Fontoura Paulo , Baudler Monika , Doody Rachelle S. 
Published: December 2022

AbstractBackgroundGantenerumab, a human monoclonal antibody targeting aggregated beta‐amyloid (Abeta), is a potential disease‐modifying treatment for early (prodromal‐to‐mild) Alzheimer’s disease (AD). SCarlet RoAD (NCT01224106) and Marguerite RoAD (NCT02051608) were two Phase III trials which assessed the efficacy and safety of subcutaneous, low‐dose gantenerumab in participants with prodromal and mild AD, respectively, for up to 2 years. Following a gap period gantenerumab treatment was continued with uptitration to a dose of 1,200 mg monthly in open‐label extensions (OLE), which demonstrated substantial Abeta removal by positron emission tomography without new or unexpected safety findings. The aim of this work is to investigate the pharmacodynamic effects of gantenerumab on plasma markers for amyloid and tau during both double‐blind and OLE periods.MethodWe evaluated the pharmacodynamic effects of subcutaneous gantenerumab on blood‐based biomarkers for amyloid and tau proteins in plasma samples collected once every year from participants who completed the double‐blind periods of SCarlet RoAD and Marguerite RoAD and participated in the OLE for up to 3 years. We measured Abeta(1–42) and phosphorylated Tau (pTau) in plasma samples using prototype Elecsys® immunoassays from Roche Diagnostics.ResultPlasma Abeta(1–42) increases by 106% (95% confidence interval [CI]: 48% to 163%) in SCarlet RoAD and 63% (95% CI: 49% to 77%) in Marguerite RoAD after 3 years of OLE treatment. Plasma pTau decreases by 24% (95% CI: –44% to –4%) in SCarlet RoAD and 11% (95% CI: –23% to +2%) in Marguerite RoAD after 3 years of OLE treatment.ConclusionChronic treatment with 1,200 mg subcutaneous injections of gantenerumab every 4 weeks increases levels of plasma Abeta(1–42) and decreases levels of plasma pTau consistently across both studies.
Implementation of Blood‐Based Biomarker Assays to Deliver Consistent and Comparable Data
Authors: Russ Kristen A , Stecker Mara , Olson Chelsea , Foroud Tatiana M. , Dage Jeffrey L. 
Published: December 2022

AbstractBackgroundImplementing biomarkers for Alzheimer’s Disease (AD) is an important area of research that will enhance the ability to accurately characterize the disease with the goal of earlier detection and treatment. Analytical validation is the first step to determine the measuring range, specificity, precision, and matrix effects of biomarker assays. Studies on analyte stability and performance bridging when key reagents are changed are critical to deliver reliable and consistent data over time. The goal of these studies is to demonstrate the performance of the assays implemented in the NCRAD Biomarker Assay Laboratory (BAL).MethodSamples were collected from patients with AD (N=14) and from healthy control subjects (N=19) by the Indiana Biobank. Samples were assayed on the Quanterix Simoa HD‐X platform using the Simoa Nf‐light Advantage Kit and P‐tau181v2 Advantage Kit to determine neurofilament light chain and P‐tau 181 concentrations. Five samples were chosen to span high, medium, and low concentrations for the validation method. Sets of 3 plates were run on two separate days using kits of the same lot number and same 5 samples. Validation assessed precision, parallelism, protein recovery, dilutional linearity, and sensitivity. In addition, our validation method allowed assessment of intra and inter batch variability. Euroimmun Beta‐Amyloid 1‐40 and 1‐42 ELISA kits were also assessed.ResultThe Nf‐Light Advantage Kit precision data coefficient of variation (CV) was less than 7% within plates and less than 8% percent within batches. The CV for precision between the runs on both days was less than 10%. The P‐tau181v2 Advantage assay precision data CV was less than 7% within plates and less than 10% within batches. The CV for total precision between runs on both days was less than 10%. Dilutional linearity, protein recovery, sensitivity, and parallelism were within acceptable levels.ConclusionThe validation studies of the commercially available Simoa Nf‐light and P‐tau181v2 Advantage Kits demonstrate the performance of these assays as implemented within the NCRAD BAL. The stability and bridging studies illustrate how the assays will be kept performing over time to deliver consistent and reliable data for researchers submitting samples for analysis. Supported by U24 AG021886 and UL1TR002529.
Baseline risk factors for developing ARIA‐E from the SCarlet RoAD and Marguerite RoAD open‐label extension studies
Authors: Lyons Marco , Neve Anuja , Huang Zhiyue , Das Bibha , Wojtowicz Jakub , Bullain Szofia 
Published: December 2022

AbstractIntroductionTreatment‐induced Amyloid‐Related Imaging Abnormalities‐Edema (ARIA‐E) are identified risks of N‐terminus anti‐amyloid antibodies, with reported overall incidence in Alzheimer’s disease (AD) trial participants of up to 40%. Known risk factors for developing ARIA‐E include apolipoprotein‐E‐e4 (APOE e4) carrier status, higher anti‐amyloid antibody dose, and baseline microhemorrhage burden.BackgroundSCarlet RoAD (SR) (NCT01224106) and Marguerite RoAD (MR) (NCT02051608) open‐label extensions were designed to investigate the long‐term safety and biomarker impact of gantenerumab 1,200mg q4w. To generate safety data that would inform future pivotal study design (GRADUATE trials [NCT03444870, NCT03443973]), five titration regimens were studied (Figure 1). ARIA‐E incidence varied across treatment arms; here we investigated potential baseline risk factors for ARIA‐E.MethodsBaseline risk factors were selected for analysis based on those previously reported in the literature as potential individual characteristics. Univariate logistic analysis was used to identify baseline risk factors and multivariate logistic analysis to assess the independence of identified risk factors.ResultsIn univariate logistic analysis, identified baseline risk factors for ARIA‐E in both studies were APOE e4 carrier status and presence of one or more microhemorrhages (Tables 1 and 2). Homozygous APOE e4 carriers were at higher risk than heterozygotes (Tables 1 and 2). Multivariate logistic analysis showed that presence of APOE e4 alleles, or one or more microhemorrhages at baseline were independent risk factors (Tables 3 and 4). Participants with both risk factors had a higher ARIA‐E onset risk than those with one or none. Age, race, sex, and body mass index were not identified as baseline risk factors for ARIA‐E (Tables 1 and 2).ConclusionAPOE e4 carrier status, in particular homozygous status, and microhemorrhage presence were identified as independent, non‐modifiable, and cumulative baseline risk factors for ARIA‐E. Taking into consideration these non‐modifiable and modifiable (speed of titration) risk factors as well as the convenience of a universal regimen for all participants, an optimized trial design with a single 9‐month titration was selected for GRADUATE trials. This optimized trial design aims to maximize exposure for all participants including individuals at higher ARIA‐E risk while offering a simple regimen for all. Results of GRADUATE trials are expected by end of 2022.