bluuebunny/crossref_metadata_2025_split huggingface dataset:
“Unraveling the Neuroprotective Mechanism of Dioscorea bulbifera (DB) in Alzheimer’s Disease (AD) Caused by Estrogen Loss: An Integrated Network Pharmacology Investigation and Experimental Validation”
Authors: Chowdhury Mayank Roy , Tiwari Anamika , Karamveer Karamveer , Dubey Govind Prasad , Tiwary Basant Kumar , Vijaykumar Sudarshana Deepa 
Published: December 2023

AbstractBackgroundAlzheimer’s disease (AD) is a leading cause of dementia, characterized by cognitive decline, and is more prevalent in women, possibly due to estrogen loss after menopause. Dioscorea bulbifera (DB), a medicinal plant, has been proposed as a potential treatment for AD. However, the underlying mechanism of action of DB and its neuroprotective effects in AD, particularly in the context of estrogen loss, remain unclear.MethodIn this study, we employed an integrative network pharmacology approach to predict the mechanism of action of DB in AD. Using a collection of AD‐related genes and predicted DB targets, we identified putative targets, direct regulatory targets, and potential regulatory targets of DB. Pathway‐enrichment analysis was performed to elucidate the pivotal pathways involved in DB’s treatment of AD. Molecular docking was conducted to verify the interactions between the core targets and the active ingredients of DB. In vivo experiments were conducted using ovariectomized rats induced with scopolamine to evaluate the neuroprotective effects of DB. Acetylcholine (Ach) and serum estradiol levels were quantified using ELISA.ResultOur results identified 132 putative targets, including 68 direct regulatory targets and 25 potential regulatory targets of DB for the treatment of AD. Pathway‐enrichment analysis revealed that neurotransmitter clearance in the synaptic cleft was a crucial pathway in the treatment of AD with DB. Molecular docking further supported the interactions between the core targets (ESR1, APP, GSK3β, BACE1, AChE, and MAOB) and the active ingredients of DB. In vivo experiments using ovariectomized rats induced with scopolamine demonstrated the neuroprotective effect of DB and validated the predicted mechanism of action.ConclusionOur findings provide experimental support for the predicted mechanism of action of DB in AD caused by estrogen loss, and validate its neuroprotective effects using behavioral tests and ELISA in ovariectomized rats. DB may hold promise as a potential therapeutic option for AD, particularly in the context of estrogen loss, and further research is warranted to explore its full potential in AD treatment.
A group of pancreatic islet β cell‐like neurons are vulnerable to energy deficiency
Authors: Cai Wenwen , Sang Shaoming , Zhong Chunjiu 
Published: December 2023

AbstractBackgroundAlzheimer’s disease (AD) bear resemblance to the diabetes mellitus for that both of them exhibit beta‐amyloid (Aβ) deposition, insulin resistance and glycometabolic disorder. Peripheral islet β cells produce insulin and islet amyloid peptides, but whether there is a group of neurons in the brain like islet β cells is not clear.MethodHybridize APP/PS1 transgenic mice and CaMKII‐CreERT2/+
;Tpkfl/fl
strain, with tamoxifen induced Tpk knockout at 6 months of age, to form a model of energy deficiency. Labeling neuron and microglia with NeuN and Iba1 antibody, and immunofluorescence was used to observe Aβ, insulin‐like growth factor expression. TUNEL staining was applied to test cell apoptosis.ResultWe found that layer 5 cortical pyramidal neurons are strongly marked by Aβ antibody, 4G8, in APP/PS1 transgenic mice. Immunofluorescence showed that these 4G8‐positive neurons colocalized with insulin‐like growth factor 1/2 and highly expressed prohormone convertase 2. Further, we conditionally knocked out Tpk gene, a key gene involved in glucose metabolism, in excitatory neurons of APP/PS1 mice. Over time, NeuN and Iba1 labeling showed that the significant loss of neuron and activation of microglia happened in layer 5 cerebral cortex at the earliest. Additionally, the 4G8‐positive neurons in this layer were stained by TUNEL and markedly reduced in the early stage.ConclusionWe found a group of islet β cell‐like neurons that are vulnerable to glucose energy impairment, suggesting a group of vulnerable neurons in sporadic AD, and implicating the cytological mechanism of association between AD and diabetes.
Quantitative Amyloid‐PET in Real‐World Practice: Lessons from the Imaging Dementia—Evidence for Amyloid Scanning (IDEAS) study
Authors: La Joie Renaud , Mundada Nidhi S. , Blazhenets Ganna , Mejía‐Perez Jhony Alejandro , Schonhaut Daniel R , Zeltzer Ehud , Soleimani‐Meigooni David N. , Cho Hanna , Ranasinghe Kamalini G , Windon Charles , Yadollahikhales Golnaz , Iaccarino Leonardo , Koeppe Robert , Carrillo Maria C. , Hanna Lucy , Gatsonis Constantine , March Andrew , Siegel Barry A , Hillner Bruce E , Whitmer Rachel A. , Rabinovici Gil D. 
Published: December 2023

AbstractBackgroundAmyloid‐PET quantification was developed in research settings using highly selected samples, harmonized acquisition protocols, and MRI‐based preprocessing. We aimed to analyze scans from IDEAS, a large‐scale, real‐world study of amyloid‐PET. Major challenges lie in scans being acquired on various PET/PET‐CT/PET‐MR scanners without standardization of acquisition or reconstruction protocols, and without MRI to preprocess data.Method18,295 Medicare beneficiaries with MCI or dementia underwent PET with [18F]florbetapir, [18F]florbetaben, or [18F]flutemetamol at 343 facilities. Sites shared 10,700 raw scans with their visual interpretation (positive or negative) by local radiologists/nuclear medicine physicians. Scans were processed using a PET‐only pipeline, which derives Centiloid based on a cortex‐to‐cerebellum tissue ratio in template space. Processed scans underwent standard visual quality control by 2 raters (Fig 1a‐b), and flagged scans were reviewed in a consensus meeting to discuss troubleshooting options. Injected dose and time between tracer injection and PET acquisition start were obtained from DICOM file header.Result9,963 scans (93%) were successfully pre‐processed with default parameters (Fig 1a) and 403 additional scans (4%) were included after manual intervention (Fig 1c). 339 scans (3%) were excluded because of technical artifacts or major bilateral lesions (Fig 1c). The final sample (n = 10,361) is described in Table 1, with example scans in Fig 1d. Centiloids showed the expected bimodal distribution (Fig 2a) and differentiated visually positive from negative scans (median = ‐2 versus 74 CL; area under the curve = 0.913, Fig 2b). PET acquisition generally followed tracer‐specific FDA recommendations for injected dose and acquisition time, but major variability was observed (Fig 2c). Centiloid values were independent from injected dose but were higher in patients scanned at later time windows for [18F]flutemetamol, resulting from known slow tracer kinetics (Fig 2c).ConclusionMRI‐free, amyloid‐PET quantification in a real‐world setting was feasible, with results conforming to expected distribution of Centiloid values and concordant with visual reads. However, greater standardization of PET acquisition than is currently required by FDA labels will be needed to reliably quantify amyloid PET in clinical practice (e.g., to monitor response to amyloid lowering therapy). The IDEAS dataset will be made available via the Global Alzheimer’s Association Interactive Network in 2023.
Genome‐wide association study on Alzheimer’s disease related cognitive, fluid, and neuropathology biomarkers in the African American population
Authors: Mu Shizhuo , Bao Jingxuan , Wen Zixuan , Yang Shu , Hohman Timothy J. , Huang Heng , Thompson Paul M , Saykin Andrew J. , Davatzikos Christos , Kim Dokyoon , Shen Li ,   for the Alzheimer’s Disease Neuroimaging Initiative and the AI4AD Initiative
Published: December 2023

AbstractBackgroundAlzheimer’s disease (AD) is a neurodegenerative disorder that progresses over time, but its exact cause remains unknown. While risk genomic loci for AD‐related biomarkers have been identified in previous studies, these findings have mostly been based on European cohorts. As a result, there is limited research on the African American (AA) population. To address this research gap, we conducted a Genome‐Wide Association Study (GWAS) using whole genome sequencing (WGS) data from Alzheimer’s Disease Sequencing Project (ADSP) to identify AD‐related variants in the AA population.MethodWGS data and harmonized phenotypes from the cognitive, fluid biomarker, and neuropathology domains were downloaded from the ADSP database. Quality control (QC) was performed on the WGS data through removing high missing call rate SNPs, rare genetic variants, genetically closely related subjects, subjects with high missing call rate, and genomic loci that failed the Hardy‐Weinberg equilibrium among cognitive normal cohort. After QC 9,815,631 SNPs and 33,324 subjects were preserved. A total of 5,397 subjects in AA population were selected for the subsequent GWAS analysis. Scalable and Accurate Implementation of Generalized mixed model (SAIGE) was used to perform association tests between genetic variants and 39 phenotypic traits controlled for age, sex, and the first 10 principal components. Functional mapping and annotation (FUMA) was used to perform the post GWAS annotations.ResultThirty‐nine phenotypic traits from cognitive, fluid biomarker, and neuropathology domains were screened but only the “infarcts and lacunes”, “PD braak (dichotomous)”, and “whole brain vascular disease” of the neuropathology data had significant GWAS signals. We identified one risk locus for each of the phenotypic traits: lead SNP rs7604487 significantly associated with “infarcts and lacunes”; lead SNP rs7093080 significantly associated with “PD braak (dichotomous)”; and lead SNP rs623123 significantly associated with “whole brain vascular disease” (Figure 1). These associations were insignificant in the ADSP cohort with European ancestry.ConclusionOur GWAS on AD related biomarkers identified three genetic loci associated with multiple neuropathological processes among the AA population. These findings have a potential to contribute to a better understanding of the AD genetic risk in the AA population. It warrants further investigation to replicate the discovery in independent cohorts.
Post‐secondary Education as a Modifiable Risk for Dementia: Birth Cohort and Gender Findings from the Health and Retirement Study
Authors: Smith Jacqui , Larkina Marina , Sonnega Amanda 
Published: December 2023

AbstractBackgroundEducation and gender are well‐known predictors of cognitive functioning after age 60, but multiple mechanisms underlie these associations. Research on dementia prevalence in the United States has highlighted the importance of considering historical changes in the quantity (years) of childhood education in potentially delaying diagnosis. Less attention has been given to gender differences in post‐secondary education despite considerable increases since the 1970s in the completion of university degrees by women.MethodWe examined new data for two cohorts of men and women in the Health and Retirement Study (HRS) about the types and content (field of study) of their college degrees. College information was collected in a Life History Mail Survey (2015‐2017). Cognitive status was assessed on a 27‐point scale in tests conducted in contingent biennial interviews (2016, 2018). Test scores were classified to indicate normal function, cognitive impairment (MCI / CIND) or dementia based on the validated HRS Langa‐Weir algorithm. The analytic sample of 9213 (60% women; 40% men) with complete data included individuals born before 1948 (n = 4662; mean age at cognitive test = 79; age range 69‐107) and Baby Boomers born 1948 to 1959 (n = 4551; mean age at cognitive test = 62).ResultsAs expected, compared to the older cohorts, more Baby Boomers had post‐secondary education (44% vs 52%; p <.001). Men in the older cohort were more likely to have a Bachelor or higher‐level degree than women, but gender was not a significant predictor of degree type in the Baby Boomers. Cohort disaggregated analyses predicting cognitive function revealed that having a BA/BSc degree provided more protection against cognitive impairment for Baby Boomer women than for men with the same degree (p < .001). College majors were gendered and significantly accounted for variance in late‐life cognitive status depending on specialization.ConclusionsThe birth cohort and gender disparities in post‐secondary education revealed in our analyses provide new insight into modifiable aspects of education beyond childhood. Future research should consider the quality and timing of college education and subsequent employment histories as life course factors that differentiate trajectories of cognitive aging and transition to dementia.
Polygenic risk for Alzheimer’s disease is associated with increased cerebrospinal fluid levels of amyloid‐beta‐40
Authors: Howard Erica , Moody Jena N , Hayes Jasmeet P 
Published: December 2023

AbstractBackgroundAlzheimer’s disease (AD) is associated with the accumulation of neuropathological beta‐amyloid (Ab) plaques, which is thought to be caused by an imbalance between Ab overproduction and dysfunctional Ab clearance. Both animal and human studies have shown that increased cerebrospinal fluid (CSF) levels of Ab peptides, especially Ab‐40 and Ab‐38 due to their high solubility, may be indicative of overall Ab dysregulation in preclinical AD, years before pathological Ab plaques begin to aggregate. The apolipoprotein E (APOE) e4 allele, which is the strongest genetic risk factor for AD, has been linked to impaired Ab clearance and disruption of the amyloid precursor protein (APP) pathway that is responsible for Ab production. However, the association between early Ab dysregulation and other genetic risk variants remains understudied. Thus, we aimed to explore whether genetic risk for AD is related to early markers of Ab overproduction by examining associations between polygenic risk scores (PRS) and CSF Ab‐40 and Ab‐38 in an AD‐vulnerable population.MethodWe selected 88 non‐demented Veterans (Age: M = 68.22, SD = 3.75 years) from the Alzheimer’s Disease Neuroimaging Initiative‐Department of Defense (ADNI‐DOD) database with available genetic markers and CSF measures for Ab‐40 and Ab‐38. Genetic propensity for AD was assessed using genome‐wide PRS, both with and without the APOE region, employing a p‐value threshold < 0.01. CSF Ab concentrations were measured using a 2D‐UPLC‐tandem mass spectrometry method outlined by ADNI‐DOD. Partial spearman’s correlations related PRS to CSF Ab‐38 and Ab‐40 levels adjusting for age.ResultCSF Ab‐40 levels were positively associated with PRS for AD (rhopartial = 0.22, p = 0.037). When variants in the APOE region were excluded from the score, the relationship between CSF Ab‐40 and PRS remained significant (rhopartial = 0.23, p = 0.035). The relationship between PRS for AD and CSF Ab‐38 levels was not significant, regardless of whether APOE regions were included in the score (all p’s > 0.1).ConclusionGenetic risk for AD may lead to early Ab overproduction, as evidenced by elevated CSF Ab levels, particularly Ab‐40. Other genetic variants, in addition to APOE, may play an integral role in disrupting the APP pathway and dysregulating Ab production.
AB1601 Phase 2 Study of ABvac40, an Anti‐Aβ40 Vaccine: Safety and Immunogenicity of a Cross‐Over Extension
Authors: Pascual‐Lucas María , Lacosta Ana María , Canudas Jesús , Montañés María , Allué Jose A , Sarasa Leticia , Molina Elisabet , Castillo Sergio , Sarasa Manuel , Terencio Jose , Boada Mercè 
Published: December 2023

AbstractBackgroundAmyloid‐β (Aβ) immunotherapy is a promising strategy for treating Alzheimer’s disease (AD). Previous studies suggested that Aβ40 could have an important role in AD, especially in relation to amyloid deposition in blood vessels in AD. The AB1601 (NCT03461276) is a multicenter, randomized, double‐blind, placebo‐controlled, phase 2 study in patients with amnestic mild cognitive impairment (a‐MCI) or very mild AD (vm‐AD) which investigated the safety, tolerability and immunogenicity of repeated subcutaneous injections of ABvac40, a vaccine targeting Aβ40. The 24‐month study (Part A) showed that ABvac40 was safe, well‐tolerated and highly immunogenic. Here, an additional 18‐month cross‐over study (Part B) was conducted to evaluate safety, tolerability and immunogenicity of ABvac40 in patients randomized to placebo in Part A (Delayed start group), and to assess safety and immunogenicity of a delayed booster of ABvac40 in ABvac40‐treated patients in Part A (Booster group).MethodA total of 124 patients with a‐MCI (N = 80) or vm‐AD (N = 44) were initially included in Part A. Seventy‐seven out of 101 patients who completed Part A transitioned to Part B. Safety assessments included the frequency of amyloid‐related imaging abnormalities (ARIA). Immune response was assessed by quantification of specific anti‐Aβ40 antibodies in plasma samples.ResultABvac40 continued to show a favorable safety profile. Specifically, no ARIA‐E was reported and ARIA‐H incidence was low, equally distributed in both groups, and similar to the placebo group (Part A). Delayed start group showed a strong and specific immune response, with a time course equivalent to the ABvac40 group in Part A. A delayed booster of ABvac40 elicited a large increase in anti‐Aβ40 antibody plasma levels, exceeding the concentrations observed throughout the active dosing phase of Part A.ConclusionThe cross‐over extension of the AB1601 Phase 2 study confirmed the excellent safety and tolerability profile of ABvac40, making this vaccine a potential candidate to be combined with other disease‐modifying therapies. Results on immunogenicity supported those obtained in Part A, demonstrating that ABvac40 elicited a strong, specific, sustained and boostable immune response. This could have important implications for long‐term treatments, especially in the context of preventive approaches. Additional exploratory efficacy results of Part B are expected in Q4‐2023.
Plasma pTau217: single vs multiple phospho‐site assays.
Authors: Benedet Andrea L. , Pola Ilaria , Triana‐Baltzer Gallen , Molfetta Guglielmo Di , Arslan Burak , Rahmouni Nesrine , Tissot Cécile , Therriault Joseph , Servaes Stijn , Pascoal Tharick A. , Kolb Hartmuth C. , Jeromin Andreas , Blennow Kaj , Zetterberg Henrik , Ashton Nicholas J. , Rosa‐Neto Pedro 
Published: December 2023

AbstractBackgroundBlood biomarkers have gained much attention in recent years given their increasing ability to indicate amyloid pathology and excellent performance in distinguishing diagnostic groups in the context of Alzheimer’s disease (AD). Plasma pTau217 has been considered the best candidate biomarker to serve as diagnostic and prognostic tool for clinical trials. However, biomarker assays targeting tau phosphorylation on Thr217 may differ because of their composition (e.g., targeting multiple or single phosphorylation sites) which may lead to distinct associations with pathology. Thus, we aimed to compare two plasma pTau217 immunoassays that differ in regard to their target specificity.MethodParticipants from the TRIAD cohort with available cross‐sectional plasma and imaging data, incorporating within the AD spectrum, were included in this study (Young = 25;CU‐ = 107;CU+ = 32;MCI+ = 42;AD+ = 47;MCI‐ = 19). Plasma pTau was quantified using the assays from Janssen (pTau217+; which exhibits enhanced signal with co‐phosphorylation of pTau212) and from ALZpath (single phosphorylation on pTau217), both performed on the Simoa platform. Amyloid and tau pathologies were indexed by PET using [18F]AZD4694 and [18F]MK6240, respectively. ANCOVA compared biomarker values across groups, Spearman rank tested the correlations between them. Linear regression models (LM) evaluated the association between plasma and PET biomarkers globally and at the voxel level.ResultBiomarker levels (fold mean of CU‐) were comparable across diagnostic groups, showing the expected increases in amyloid positive groups. Both plasma assays were highly correlated with amyloid (Fig.1), which was also observed on the LM adjusted by age and sex, and on the voxel‐wise analysis (Fig.2). Associations with tau PET SUVR (medial temporal) were also significant and showed similar distribution between the two pTau assays. When neocortical tau was evaluated, however, pTau217+ had a better association as well as higher correlation coefficients within amyloid+ (Fig.3) and neocortical tau+ groups than did ALZpath pTau217.ConclusionIn general, pTau217 assays with different antibody specificity showed very similar associations with PET. However, pTau217+ achieved a better association with neocortical tau as compared to ALZpath pTau217. A biomarker targeting multiple phosphorylation sites might be a better proxy of advanced tau, therefore may offer improved ability to detect and exclude participants with advanced AD pathology for clinical trials.
Dementia risk‐stratification in a large, decentralized cohort of aging individuals with subjective cognitive complaints from the INTUITION brain health study
Authors: Gabelle Audrey , Butler P. Monroe , Saha‐Chaudhuri Paramita , Brown Roland , Hobbs Matt , Becker Andrew , Bianchi Matt , Lenyoun Hanson , Hughes Richard , Belachew Shibeshih ,   Intuition Scientific Committee
Published: December 2023

AbstractBackgroundSubjective cognitive complaints (SCC) signal risk of objective cognitive decline. To better understand the bio‐behavioral factors that signal cognitive trajectories at‐risk for the earliest stages of Alzheimer’ disease, there is a need for well‐phenotyped large‐scale population‐based cohorts with longitudinal assessments.MethodFrom the INTUITION decentralized observational brain health study (NCT0505895), using app‐collected self‐report data, we compared the demographic, clinical, and neuropsychological profiles of 2045 SCC versus 4090 age‐ and education‐matched cognitively normal (CN) participants. The SCC cohort was defined by age (> = 50 years) and presence of significant cognitive concerns based on total scores> = 4 on the 14‐item Cognitive Function Instrument (CFI‐14). Using customized assessments from Cambridge Cognition, Pattern Recognition Memory (PRM), Paired Associates Learning (PAL), Spatial Working Memory (SWM), and Match‐to‐Sample (MTS) tests were performed. SCC participants were stratified and compared by presence or absence of dementia risk factors (first‐degree family history of dementia (FH+/FH‐) or 2+ cardiovascular risk factors (CVRF2+/CVRF2‐)).ResultCognitive and neuropsychiatric symptom‐burden were greater among the SCC cohort compared to CN participants (e.g., E‐Cog‐12: 1.8(0.5) vs 1.2(0.3), pathological PHQ2 (Total> = 3): 14% vs 2.7%, pathological GAD‐2(Total> = 3): 11.8% vs 1.9%, respectively p<0.001). Lifestyle factors differed, with SCC participants reporting lower level of physical activity, higher substance use and impaired sleep, relative to CN. Among SCC participants the prevalence of CVRF2+ and FH+ were 53.2% and 37.8%, respectively; and 43% (CVRF2+) and 33.5% (FH+) among CN. Among SCC, individuals with CVRF2+ were more likely to be older, male, and with higher rates of anxiety/depression symptoms. Mean total CFI‐14 scores were similar between FH+/FH‐ or CVRF2+/CVRF2‐, but item‐level CFI profiles differed (e.g., word‐finding complaints in FH+/CVRF2+). SCC scored lower on key CANTAB outcomes (e.g., PAL/PRM) evaluated compared to CN. Both CVRF2+ and FH+ participants with SCC performed worse on cognitive measures of learning (SWM) and attention (MTS) compared to CVRF2‐ and FH‐ respectively.ConclusionIn a large, decentralized cohort, SCC was associated with higher burden of modifiable and non‐modifiable risk factors. First‐degree family history of dementia and cardiovascular disease, when coupled with SCC, revealed more severe measurable objective cognitive deficits. Future work will assess individual longitudinal cognitive trajectories.