bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genetically Proxied Angiotensin‐Converting‐Enzyme Inhibition is Potentially Causal for Alzheimer Disease: A Mendelian Randomization Study
Authors: Nassan Malik , Piras Ignazio , Rogalski Emily J. , Geula Changiz , Mesulam M.‐Marsel , Dashti Hassan , Saxena Richa , Huentelman Matthew J 
Published: December 2022

AbstractBackgroundAngiotensin‐converting enzyme (ACE) has been implicated in the pathogenesis of Alzheimer disease (AD), in which ACE plays a role in metabolizing Amyloid Beta (AB). Genetic variants in the ACE locus have also been associated with AD. The effect of ACE inhibitors on AD risk remains unclear. We sought to investigate the potential causal relationship between ACE inhibition and AD and other neurodegenerative disorders using a mendelian randomization (MR) approach.MethodA genetic proxy for ACE inhibition (MR exposure) was generated using 17 single nucleotide polymorphisms (SNPs) in the ACE gene that were previously associated with lower ACE blood levels in a candidate gene study (n = 4,147; adjusted‐P < 0.05). Summary genome‐wide association study (GWAS) statistics for AD (111,326 cases, 677,663 controls), Frontotemporal dementia (FTD) (3526 cases, 9402 controls) and Lewy body dementia (LBD) (cases 2591, controls 4027) were used as proxies for the MR outcomes. Inverse weighted variance MR was performed to test the potentially causal relationship between the exposure and outcomes. Sensitivity analyses were completed to test the robustness of the results.ResultACE inhibition was significantly associated with increased risk of AD (OR = 1.07, P = 0.0000005); with robust and consistent effects in all sensitivity analyses. Using leave one out method; rs4343 (A allele) showed the strongest effect. rs4343 is in mild linkage disequilibrium with the SNP associated at genome wide significant level with AD rs4277405 (R2 0.35). Rerunning the MR analysis on the AD cohort after removing rs4343 continued to show significant results (OR = 1.04, P = 0.02). ACE inhibition was also associated with increased risk for FTD (OR = 1.16, P = 0.009), but the findings were not robust in some sensitivity analyses, possibly due to lower sample size of FTD cohort. ACE inhibition was not associated with LBD.ConclusionThis is the first study to provide robust genetic evidence for the potentially causal relationship between ACE inhibition in the blood and the diagnosis of AD. These results should encourage further investigation of the potential neurodegenerative side effects of ACE inhibition; and further suggest ACE related pathways as pharmacological targets for treatment and/or prevention of AD.
Validation of a fully automated lab developed test for plasma phospho‐tau 181 levels for Alzheimer’s disease diagnosis
Authors: Malyavantham Kishore , Brock Mary , Brunelle Lynn A , Miller Mike , Marble Hetal , Wilson David , Teunissen Charlotte E. , Mattoon Dawn 
Published: December 2022

AbstractBackgroundThe potential usefulness of plasma phosphorylated tau (pTau) measurements for identifying individuals likely to be on the Alzheimer’s disease (AD) continuum is evident from recent literature. Here we report the validation of an immunoassay for measurement of pTau181 in human plasma that will aid in the evaluation of Alzheimer’s pathology in cases presenting with mild cognitive impairment.MethodThe Simoa pTau‐181 assay is a fully automated 2‐step digital sandwich immunoassay that utilizes paramagnetic beads with capture antibodies and biotinylated detector antibodies. Digital detection is achieved using Simoa discs via SβG (Streptavidin‐ß‐galactosidase) and RGP (Resorufin‐β‐D‐galactopyranoside) amplification of specific pTau181 immune complexes. Harmonization to the Simoa pTau‐181 method described by Karikari et al (Mol Psychiatry. 2021;26(2):429‐442) using 80 samples, establishes commutability with published results from ADNI cohorts. Analytical validation on HD‐X instrument followed CLSI guidelines. Thirty‐four AD cases from the Amsterdam Dementia Cohort (age 66 ± 8 years) diagnosed according to the NIA‐AA diagnostic AD criteria and had a CSF biomarker‐confirmed AD diagnosis, 36 age‐ and sex‐matched (age 66 ± 8 years) cognitively healthy controls from the Dutch Brain Research Registry were included for clinical validation of this LDT.ResultThe limits of detection (LoD) and quantification (LoQ) were 0.056 pg/mL and 0.276, respectively. Repeatability and reproducibility across 3 reagent lots using samples across the measuring range were 4.25% (95%CI:2.84‐5.65), 9.42% (95% CI: 4.46‐14.37) respectively. Linearity was demonstrated per CLSI EP06‐A, as ≤15% deviation at all dilutions. Cross reactivity against full length unphosphorylated‐Tau441 and synthetic peptides for pTau231 and pTau217 epitopes was below LoQ. ROC analysis resulted in a high AUC (area under the curve) of 0.897 (95% CI 0.825 to 0.969). Applying the cut‐offs described in Karikari1 (17.7 pg/mL) for this cohort resulted in a sensitivity of 94%, specificity of 72%.ConclusionThis test demonstrated acceptable analytical performance for CLIA laboratory implementation. High AUC of 0.897 to discriminate AD from non‐AD cases helps both rule‐in or rule‐out scenarios, and further allows for setting of cut‐off values that not only take the pretest probability, impact on screening algorithm, treatment protocols into consideration but also the costs incurred by misdiagnosis.
ENVISION: A phase 3b/4 randomized, double‐blind, placebo‐controlled, parallel‐group study to verify the clinical benefit of aducanumab in participants with early Alzheimer’s disease
Authors: Murphy Jennifer , Aisen Paul , Barkhof Frederik , Castrillo‐Viguera Carmen , Cheng Wenting , Cohen Sharon , Hansson Oskar , He Ping , Iwatsubo Takeshi , Jaeger Judy , Montenigro Philip H. , Rubel Carrie E. , Mummery Catherine J. , O'Gorman John , Racine Annie M , Vellas Bruno , Wu Shuang , Haeberlein Samantha Budd 
Published: December 2022

AbstractBackgroundAducanumab is a human monoclonal antibody selective for aggregated forms of amyloid beta approved in the United States by the Food and Drug Administration (FDA) for the treatment of Alzheimer’s disease on June 7, 2021 under the accelerated approval pathway, which requires a randomized‐controlled trial with an appropriate control to verify the clinical benefit of aducanumab. On March 25, 2022 the sponsor submitted the final protocol for this trial, named ENVISION, to the FDA.MethodENVISION (NCT05310071) is a multicenter, randomized, double‐blind, placebo‐controlled, parallel group study in participants with mild cognitive impairment due to Alzheimer’s disease (Stage 3) and mild Alzheimer’s disease dementia (Stage 4), designed to verify the clinical efficacy and safety of aducanumab. Key enrollment criteria include MMSE score of 22‐30, age 60‐85, CDR‐G of 0.5 or 1.0, regardless of ApoE ε4 status. Participants will be randomized, to receive aducanumab or placebo in a 2:1 ratio and will be titrated to 10 mg/kg aducanumab or placebo by intravenous infusion every 4 weeks for a treatment duration of 24 months.The primary objective is to assess the clinical benefit of monthly doses of aducanumab in slowing cognitive and functional impairment as measured by change of CDR‐SB score at 18 months as compared to placebo. Key secondary endpoints include change in ADCS‐ADL‐MCI, ADAS‐Cog13, iADRS, MMSE, and NPI‐10; other secondary endpoints include change in amyloid PET and tau PET signal. Safety endpoints include incidence of ARIA events and SAEs. Exploratory endpoints include CSF and plasma biomarkers.Approximately 1512 participants will be enrolled across 220 centers globally. A racially/ethnically representative population will be included in the United States, with an enrollment goal of 18% Black/African American and LatinX/Hispanic patients.ResultENVISION will begin in Q2 2022 and read out approximately 4 years after first patient in. Primary analysis read‐out of clinical, biomarker, and safety data will be at 18 months, with additional longer‐term data on aducanumab treatment effect up to 24 months.ConclusionThe confirmatory ENVISION trial will further explore clinical efficacy, biomarker profile, and safety of aducanumab in a racially/ethnically representative population.
Drug therapy, imaging, and other aspects of clinical management change after Alzheimer’s biomarker testing in routine practice: Findings from the IMPACT‐AD BC study
Authors: Yang David , Best John R. , Chambers Colleen , Feldman Howard H. , Pettersen Jacqueline A , Henri‐Bhargava Alexander , Lee Philip E , Nygaard Haakon B. , Funnell Clark R , Foti Dean J , Hsiung Ging‐Yuek Robin , DeMarco Mari L. 
Published: December 2022

AbstractBackgroundWhile previous studies have demonstrated the effect of Alzheimer’s disease (AD) CSF testing in changing diagnosis, we lack an understanding of how this testing affects clinical management. Therefore, we assessed changes in clinical management associated with AD CSF biomarker testing when ordered as part of routine clinical management.MethodThe ‘Investigating the Impact of Alzheimer’s Disease Diagnostics in British Columbia’ (IMPACT‐AD BC) study (NCT05002699) is a longitudinal study examining the impact of AD CSF testing on clinical management, personal utility and health care economics in British Columbia, Canada. After AD CSF testing was ordered as part of routine care (where the clinical scenario met the appropriate use criteria), the patient and their physician were eligible to participate in the study. The primary outcome was the change in management (pre‐ v. post‐biomarker results) in a composite measure including 1) AD drug therapy, 2) other relevant drug therapy, 3) other diagnostic procedures, and 4) referral or counselling.ResultParticipants (n = 129) had a median age of 63 (IQR:58‐68); 49% were female. Cognitive impairment at baseline consisted of 7% with subjective cognitive impairment, 53% with mild cognitive impairment, and 40% with dementia. CSF biomarker profiles were consistent with an amyloid‐beta pathology (i.e., A+) in 72% of cases. Changes in clinical management because of testing occurred in 83% of cases including: referrals and counseling (57%), imaging (47%) and other diagnostic procedures (e.g., neuropsychological testing) (42%), and use of AD drug therapies (40%). For those with a non‐AD pre‐biomarkers diagnosis, 42% were changed to AD post‐biomarkers; for those with an AD pre‐biomarkers diagnosis, 18% were changed to non‐AD post‐biomarkers.ConclusionThis study has revealed substantial changes in clinical management as a direct result of AD CSF biomarker testing in routine care. An understanding of the implications of biomarker testing will in turn help us: improve appropriate utilization, understand the broader impacts on persons living with dementia and on the health care system, and prepare for expanded use of this testing with the availability of disease‐modifying therapeutics.
Age‐related changes in clinically relevant biomarkers in a Beagle model of Alzheimer’s disease.
Authors: de Rivera Christina , Prenderville Jack , Araujo Joseph A 
Published: December 2022

AbstractBackgroundCanine aging is associated with cognitive decline linked to several neuropathological changes that parallel those reported in Alzheimer’s disease including deposition of amyloid‐β, cerebral amyloid angiopathy, dystrophic neurites, reduced neurogenesis, neuronal loss, activated microglia and astrogliosis. Dogs also demonstrate domain specific cognitive decline with short‐term working memory and executive function impacted early in canine aging. One contributing factor of Alzheimer’s disease is neuroinflammation, including activation of microglia and astrocytes, which are also seen in canine brain aging. Microglia bind to soluble amyloid‐β oligomers and fibrils by various receptors including toll‐like receptors (TLR2, TLR4, TLR6 and TLR8), which is postulated to be part of the neuroinflammatory process in Alzheimer’s disease. Toll like receptor activation leads to downstream production and release of pro‐inflammatory cytokines through the NFκB signaling pathway. Activated astrocytes accumulate around senile plaques and release cytokines, and other cytotoxic molecules, when exposed to amyloid‐b, further contributing to the neuroinflammatory response. The current study sought to investigate whether concentrations of the following cytokines varied by age in canine biofluids; IL‐6, TNFα, IL‐8, IL‐10, and IL‐12.MethodConcentrations of the aforementioned cytokines in cerebrospinal fluid and plasma from three age groups of dogs were evaluated in the current study. The young aged group included samples from dogs under 6 years of age. The middle age group included samples from dogs between 6 and 10 years of age. The aged or senior group included samples from dogs greater than 10 years of age.Results and ConclusionThe results of the study will be presented, and we hypothesize that age‐related changes in cytokine concentrations may be used as a potential clinically relevant biomarker for evaluating the effects of putative Alzheimer’s disease therapeutics targeting neuroinflammation, particularly when used in conjunction with neuropsychological cognitive assays.
Multitarget evaluation of molecules from marine animals against Alzheimer's disease, related to gamma‐ and beta‐secretases and cathepsin B protein targets
Authors: De Blasio Paola 
Published: December 2022

AbstractBackgroundOne of the causes for Alzheimer’s disease (AD) is the secretase activity on the APP protein, producing ß‐amyloid peptides (Aß) that aggregate and accumulate in regions of the brain, causing cell death (WAKABAYASHI; STROOPER, 2008). Secretase (β and γ) inhibitors have been studied as an alternative to treatment, but they have exhibited toxicity or ineffectiveness; however, these enzymes are still considered potentially effective therapeutic targets. Besides these inhibitors, cathepsin B is considered another possible inhibitory target for its involvement in protein clearance and neuroinflammation (CHITRANSHI et al, 2021). Thus, this work aimed to analyze, by virtual screening, the inhibition of such enzymes, among molecules described from marine animals, in order to obtain a new prototype for amyloid plaques decrease.MethodMolecules from marine animals were searched in scientific articles and prepared for docking, conducted by Swiss Dock server, to predict molecular interaction with β and γ‐secretases and cathepsin B (selected on PDB). Results were analyzed by UCSF Chimera and, by predicting the molecular interaction, the molecules were selected if they were positioned in the enzyme active site, with distance lower than 3 Å and binding energy lower than ‐5 kcal/mol.ResultAmong 50 molecules, Sebastianine A obtained a positioning exactly in the active site of the β‐secretase, presenting favorable binding energy of ‐6.74 kcal/mol and the binding distance of 2.395 Å with the amino acid Thr72. Regarding the γ‐secretase, it was observed the lowest binding energy of ‐6.86 kcal/mol, and 2.42 Å to the amino acid Lys380. Lastly, in the case of cathepsin B, it was possible to identify a distance of 3.091 Å and binding energy ‐6.45 kcal/mol to the amino acid Gln25.ConclusionSebastianine A has the potential to inhibit 3 important enzymes for the AD development, in a multitarget approach, relevant for this complex disease. This result represents a promising drug candidate for this disease without cure so far.
Culture Matters in Assessment of Daily Activities: An example from Turkey in a large community sample
Authors: Ayhan Yavuz , Karahan Sevilay , Akbulut Bilal Bahadır , Topçuoğlu Esen Saka , Bilir Nazmi , Caman Ozge Karadag 
Published: December 2022

AbstractBackgroundDemographic variables such as gender and age, within their own cultural context, might play a role in the instrumental activities of daily living (IADL). Functional evaluation of the elderly requires acknowledgement of the cultural context. In this study we aimed to determine the functional activities of cognitively normal Turkish elderly in a large community sample.Method1909 people over the age of 55, with no known diagnosis of neuropsychiatric/ developmental disorder, representing Turkey’s demographic structure were recruited. Modified Mini Mental State (3MS) was used as the cognitive assessment method. MMSE scores were estimated from 3MS. Participants with an MMSE score of over 25 and over 20 for educated and undereducated population respectively were determined as cognitively normal. Lawton‐Brody Instrumental Activities of Daily Living and Functional Activities Questionnaire were used to assess instrumental activities of daily living. Ordinal logistic regression analysis was used to assess the relation between the demographic variables and IADL.ResultThe data of 1503 individuals were assessed. 28.7% of the sample were over the age of 80, females comprised 52%, and 33.5% of the individuals were undereducated. Age, gender and education were asociated with IADL. Overall, individuals over 80 years of age were less independent in all instrumental acitivities. Regarding gender, male individuals were more independent on transportation, shopping, using phone, keeping track of current events and paying attention/discussing media, while females reported more independence on food preparation, housekeeping and laundry. The level of education was associated with dependence on phone use, shopping, travelling and finance, individuals with less than 5 years of education were significantly less independent on Transportation, shopping, using phone and finance management when compared with higher educated individuals.ConclusionThe activities of daily living differed at different age, gender and education levels in Turkish population. Our results displayed differences from previous studies representing various cultures. The assessment of functional activities of daily living requires appreciation of the cultural context.
Prioritizing drug targets for Alzheimer’s Disease using a Mendelian Randomization framework integrating neuroimaging and genomics
Authors: Sreepada Lasya P ,   for Alzheimer's Disease Neuroimaging Initiative and UK Biobank
Published: December 2022

AbstractBackgroundAlzheimer’s Disease is a progressive neurodegenerative disorder that currently has no disease‐modifying treatment, partly due to inefficiencies in identifying and validating drug targets. Drugs with genetic support are more likely to succeed in pharmaceutical trials. Recent studies show that in vivo neuroimaging can capture changes in brain pathology and function before onset of cognitive symptoms, thereby serving as biomarkers for early diagnosis. Pharmaceutical intervention may be more effective if treatment is started earlier in the disease course. We aim to integrate imaging and genomic data to identify and prioritize gene targets for Alzheimer’s Disease treatment.MethodWe apply Mendelian Randomization (MR) to investigate the druggable genome: 3,000 genes encoding proteins that can be targeted with molecular compounds. Gene expression mimics low‐level exposure to compounds in individuals.We examine the causal effect of expression and protein quantitative trait loci (eQTL and pQTL) information, from public datasets like GTex, in relation to markers of Alzheimer’s Disease risk and progression using GWAS summary statistics. The analyses are performed and replicated using two independent, publicly available datasets from ADNI and UK Biobank, including matched cases and controls. Genomic data will be imputed with a standard reference genome and harmonized across studies.ResultWe will describe the dataset and analysis pipeline needed to run and validate an MR experiment that identifies gene targets for disease‐modifying treatment based on eQTL and pQTL data. We will report results of descriptive and inferential statistical analyses associating these genes with disease risk, onset, and progression using related outcome variables such as structural imaging biomarkers, clinical measures and cognitive test scores. We propose a small subset of these gene targets with the strongest MR evidence as optimal candidates for drug development research, including potential drug repurposing opportunities.ConclusionThis study will identify gene targets for prioritization or repurposing in Alzheimer’s Disease drug development and clinical trials. The proposed targets are supported by genetic evidence of implication in disease risk, onset, and progression via association with neuroimaging features and cognitive scores. These results could aid pharmaceutical trials in terms of time and financial efficiency as well as increase the potential for success.
Post‐refolding stability considerations for optimization of in‐vitro refolding: L‐asparaginase as a case study
Authors: Mihooliya Kanti Nandan , Nitika Nitika , Bhambure Rahul , Rathore Anurag S. 
Published: December 2022

AbstractBackgroundL‐Asparaginase is an essential enzyme for the food and biopharmaceutical industry. The stability, however, of L‐asparaginase is widely known to be an issue. Commercial manufacturing of any biopharmaceutical involves hold‐ups during processing, and can result in product loss if stability is an issue, as is the case with L‐asparaginase. This interplay of product intermediate stability and process design is the focus of this investigation.Methods and ResultsIn this study, we propose a strategy to simultaneously increase the refolding yield and stability of refolded L‐asparaginase so as to improve overall process yield. Using one variable at a time (OVAT) experiments, urea (6 M), solubilized inclusion bodies (15 mg/ml), refolding method (step dilution), and pH (8.6) were identified as significant process parameters. A design of experiment (DOE)‐based optimization was then performed for the refolding step. The net outcome was more than a three‐fold increase in enzyme recovery (i.e., 4.90 IU/ml) compared to unoptimized conditions (i.e., 1.26 IU/ml). Further, the L‐asparaginase process intermediate was found to be stable for more than a week at room temperature and 2–8°C, while the unoptimized sample was stable at 2–8°C but did not show any activity at room temperature after 72 h.ConclusionsThe current study elucidates how process intermediate stability needs to be given due consideration during process optimization, particularly for products such as L‐asparaginase which are labile.
A Water‐Free ITIES: Ionic Liquid/Oil Interface for Base Metal Nanostructure Formation – Zn Case
Authors: Nishi Naoya , Kuroyama Yohei , Yoshida Naohiro , Yokoyama Yuko , Sakka Tetsuo 
Published: December 2022

AbstractInvited for this issue's Front Cover is the group of Dr. Naoya Nishi of Kyoto University (Japan). The cover picture shows the water‐free liquid‐liquid interface between an ionic liquid and oil, where base metal nanostructures can be formed via the electron transfer reaction between metal ions on the ionic liquid side and reducing agents on the oil side of the interface. Read the full text of the Research Article at 10.1002/celc.202201000.