bluuebunny/crossref_metadata_2025_split huggingface dataset:
Investigating changes in fluid biomarkers in early Alzheimer’s disease: design of plasma biomarker analyses and a cerebrospinal fluid sub‐study in the evoke and evoke+ trials of semaglutide versus placebo
Authors: Cummings Jeffrey , Zetterberg Henrik , Atri Alireza , Hansen Charlotte Thim , Honore Julie Broe , Johannsen Peter , Knop Filip Krag , Raket Lars Lau , Sano Mary , Soininen Hilkka , Feldman Howard H. 
Published: December 2022

AbstractBackgroundSeveral studies have generated data supporting a role for glucagon‐like peptide 1 receptor agonists (GLP‐1RA) in the treatment of Alzheimer’s disease (AD). For example, GLP‐1RAs reduced neuroinflammation and phospho‐tau accumulation, provided neuroprotective effects, and improved cognitive function in animal model studies. In patients with AD, GLP‐1RAs preserved cerebral glucose metabolism, favorably affected cognition and cortical volume, and in post‐hoc analyses of randomized clinical trials in type 2 diabetes, reduced cognitive impairment and dementia risk. The phase 3 evoke and evoke+ trials (NCT04777396 and NCT04777409, respectively) will assess the efficacy and safety of oral semaglutide (a GLP‐1RA) versus placebo in early AD. Here, we describe how fluid biomarkers will be investigated.MethodParticipants in the randomized double‐blind, placebo‐controlled evoke and evoke+ trials (N=1,840 per trial) will be randomized 1:1 to oral semaglutide 14 mg once‐daily or matched placebo for 156 weeks. The primary endpoint is change in Clinical Dementia Rating Scale – Sum of Boxes score from baseline to week 104. In both studies, fluid biomarkers will be measured in plasma (all participants [except those in China]) and cerebrospinal fluid (CSF) (a sub‐set of participants). For plasma biomarkers, blood samples will be collected at baseline (week 0) and weeks 52, 104, and 156. For CSF biomarkers, samples will be collected before randomization and at week 78, aiming for around 210 consenting participants (Figure). In each trial, participants will be stratified by CSF sub‐study participation (yes/no) to ensure 1:1 randomization in the sub‐study population. The range of biomarkers analyzed will encompass markers of AD, neuroinflammation, neurodegeneration, blood–brain barrier integrity, oxidative stress, and vascular health (Table).ResultResults from the plasma biomarker analyses and CSF sub‐study of the evoke and evoke+ trials are expected in 2025.ConclusionThese analyses of the evoke and evoke+ studies will investigate the effects of semaglutide on fluid biomarkers in participants with early AD. The analyses will provide insights into the mechanism of action of semaglutide on neuroinflammation and neurodegeneration (and the relationship between the two) in this population.
Transcriptomic profiling of myeloid cells in Alzheimer’s Disease brain illustrates heterogeneity of microglia endolysosomal subtypes
Authors: Prater Katherine E , Green Kevin J , Sun Wei , Smith Carole L , Chiou Kenneth L , Mamde Sainath , Heath Laura M , Rose Shannon , Keene C. Dirk , Kwon Ronald Y , Snyder‐Mackler Noah , Blue Elizabeth E , Young Jessica E. , Logsdon Benjamin A , Shojaie Ali , Garden Gwenn A , Jayadev Suman 
Published: December 2022

AbstractBackgroundMicroglia‐mediated neuroinflammation contributes to disease progression in Alzheimer’s Disease (AD). Microglia demonstrate heterogeneous states with proposed beneficial, harmful, and disease‐specific subtypes. Defining the spectrum of microglia phenotypes is crucially important to the design of neuroinflammation‐modulating therapies.MethodWe performed single‐nucleus RNA‐seq on over 120,000 microglia nuclei isolated from dorsolateral prefrontal cortices collected from 12 AD and 10 controls. Nuclei were sorted for PU.1 expression using fluorescence activated nucleus sorting.ResultsWe detected several microglia clusters that expressed features of “activation” as well as three previously unrecognized microglia transcriptomic subpopulations. These newly described subpopulations are defined by predominant endolysosomal gene expression patterns heterogeneous for metabolic and inflammatory signatures. One endolysosomal subtype is more abundant in AD individuals and uniquely enriched for transcripts involved in nucleic acid detection and interferon signaling. This population is distinct from a classic inflammatory subpopulation also present in our cohort, which upregulates NFKB, TLR and interferon related pathways but does not share the endolysosomal signature. Network analysis revealed subtype specific enrichment of IRF3 and IRF5 regulomes. AD individuals also exhibited increased expression of unfolded protein response and inflammatory genes in homeostatic microglia subpopulations.ConclusionWe demonstrate significant heterogeneity in human brain microglia subtypes including identifying multiple endolysosomal subpopulations. Like neuroinflammation, alterations in the endolysosomal system have been identified as a key component of AD pathology; however, how endolysosomal dysfunction contributes to AD progression remains unresolved. Our study is the first to identify a subpopulation of microglia in human AD brain correlating endolysosomal activity and interferon pathway induction supporting a relationship between these two pathways in AD pathogenesis. These results highlight the heterogenous nature of the microglia response to AD pathology and inform efforts to target specific subtypes of microglia in the development of novel AD therapies.
Clinical validation of the Virtual Reality Functional Capacity Assessment Test – Short List (VRFCAT‐SLx) for assessment of iADL functioning in early symptomatic dementia: Baseline performance and associations with standard measures
Authors: Atkins Alexandra S , Schoemaker Dorothee , Abraham Chelsea , Flanagan Chloe , Evans Haley , Madsen Corrine , Sickel Nancy , Stevens Heather , Amaya Alexandra C , Plassman Brenda L , Loewenstein David , Welsh‐Bohmer Kathleen A. , Keefe Richard SE 
Published: December 2022

AbstractBackgroundClinical trials in preclinical and early symptomatic Alzheimer’s disease require increased precision for the assessment and monitoring of functional capacity. The Virtual Reality Functional Capacity Assessment Tool (VRFCAT) is a performance‐based assessment of function with the potential to serve this need. Prior work has demonstrated the VRFCAT’s validity and sensitivity as a measure of iADL functioning in subjective cognitive decline (Atkins et al., 2019), but pilot work in more cognitively impaired individuals indicated a risk of floor effects in some patients. The VRFCAT “Short List” (VRFCAT‐SLx) was developed to address this issue by modifying the test to reduce length and complexity. We present Baseline data from an ongoing clinical validation study of the VRFCAT‐SLx in participants with clinically characterized MCI/AD dementiaMethodAt the time of submission, participants included 77 adults (32 male; mean age = 73.29, SD = 7.52) with established diagnoses of MCI or mild AD (NIA‐AA criteria) and CDR global scores of 0.5 or 1.0. Participants completed the tablet‐based VRFCAT‐SLx and other established measures (ADCS‐ADL‐MCI, MMSE, CDR, BAC cognitive tests) at Baseline and Follow‐up. At submission, 22 participants had completed follow‐up. Statistical analyses of baseline data, reported here, examined VRFCAT‐SLx task completion rates, the frequency of “floor” level performance, and baseline correlations with standard measures.ResultMean MMSE at Baseline was 27.47 (SD = 2.0). Cognitive performance reflected diagnoses of MCI, with the greatest impairments on verbal memory (1‐1.5 SD below the normative mean). All participants were able to complete the VRFCAT‐SLx at Baseline; 97.4% of participants (all but 2) met a priori set criteria for performance validity. VRFCAT‐SLx completion time (Total Adjusted Time) was significantly correlated with partner‐reported functioning on the ADCS‐ADL‐MCI (r = ‐.48, p<.001), the CDR‐SB (r = .37, p<.001), and BAC cognitive measures including Verbal List Learning (r = ‐.42, p<.001), Delayed Recall (r = ‐.40, p<.001), Tower of London (r = ‐.45, p<.001), and Symbol Coding (r = ‐.42, p<.001).ConclusionBaseline results support the use of the VRFCAT‐SLx as a performance‐based assessment of functioning in early symptomatic MCI/AD. Strong associations between VRFCAT‐SLx scores, partner‐reported functioning, clinical staging, and cognition replicate and extend earlier findings regarding the construct validity and clinical relevance of the tool.
Is the Long‐term Impact of a Multidomain Lifestyle Intervention on Cognitive Function Mediated by Changes in Leptin and Vascular Endothelial Growth Factor Concentrations?
Authors: Espeland Mark A. , Carmichael Owen T. , Evans Joni K , Hayden Kathleen M. , Johnson Karen C , Kahn Steven , Luchsinger Jose , Marvocina Santica , Neiberg Rebecca H. 
Published: December 2022

AbstractBackgroundThe 10‐year intensive lifestyle intervention (ILI) of the Look AHEAD study resulted in a legacy of relative deficits in cognitive function among participants who entered the clinical trial with a history of cardiovascular disease or current obesity, as compared to participants assigned to the diabetes support and education (DSE) intervention. We hypothesized that levels of two weight‐sensitive proangiogenic cytokines, leptin and vascular endothelial growth factor (VEGF), which have been previously reported to be associated with cognitive function, may have been altered by the ILI and account for this concerning finding.MethodConcentrations of leptin and VEGF were determined using stored serum collected from 1,279 participants at Look AHEAD baseline, proximal to cessation of the intervention (Epoch 1), and an average of 4 years later (Epoch 2). Masked clinic staff conducted up to four standardized assessments of cognitive function at times ranging from 8 to 18 years after baseline. A composite score was derived from tests of attention, executive function, and memory. Mixed effects models were used to assess relative differences in leptin and VEGF concentrations between intervention groups and whether these accounted for changes in cognitive composite scores, overall and within subgroups defined by baseline history of cardiovascular disease or obesity.ResultIn both intervention groups, leptin concentrations increased from baseline to Epoch 1, and further between Epochs 1 and 2 (p<0.001). VEGF concentrations decreased between enrollment and Epoch 2 in both groups, and decreased substantially more between Epoch 1 and 2 in ILI than in DSE (p = 0.04). Overall, there was little evidence that leptin and VEGF concentrations were related to cognitive functioning. ILI‐DSE differences in VEGF, but not leptin, concentrations varied depending on baseline history of cardiovascular disease and obesity, but neither leptin or VEGF concentrations accounted for the relative decrements in cognitive function evident during long‐term follow‐up in participants assigned to ILI.ConclusionAmong persons with type 2 diabetes and either a history of cardiovascular disease or obesity, long‐term relative deficits in cognitive function associated with intensive lifestyle intervention are not related to differences in two weight‐sensitive proangiogenic cytokines.
Education and Cognitive Function in the United States and Mexico
Authors: Saenz Joseph 
Published: December 2022

AbstractBackgroundEducation is associated with level of cognitive ability and may improve cognition by building cognitive reserve and improving health and socioeconomic status (SES) throughout life. This analysis evaluates consistency of associations between education and cognitive domains in the United States and Mexico and asks whether associations can be explained by late‐life health and SES.MethodData includes adults age 50+ from the MexCog in Mexico (n = 2,042) and the Harmonized Cognitive Assessment Protocol (HCAP) in the United States (n = 3,267). Associations between years of education and factor scores for several cognitive domain were estimated separately for each country, with and without adjustment for multiple chronic conditions, income, and wealth.ResultIn gender/age adjusted models, a year of education was associated with having 0.11 (memory), 0.14 (executive function), 0.14 (language), and 0.13 (visuospatial) standard deviations higher cognition in the MexCog and 0.12 (memory), 0.14 (executive function) and 0.13 (language) 0.10 (visuospatial), and 0.07 (orientation) standard deviations higher cognition in the HCAP. Further adjustment for chronic conditions, income, and wealth did not affect the size or statistical significance of estimates in either country.ConclusionEducation positively related with cognition across all domains similarly in the United States and Mexico. Results suggest a direct effect of education on cognitive ability that is not eliminated by reducing educational disparities in later life health and SES.
Characterising heterogeneous spatiotemporal progression patterns of Alzheimer’s disease using Subtype and Stage Inference
Authors: Young Alexandra L. 
Published: December 2022

AbstractBackgroundAlzheimer’s disease is heterogeneous in clinical syndrome, biomarker signature, and pathology. Disentangling this heterogeneity is challenging because multiple underlying factors contribute to the observed heterogeneity, including variability in disease subtype and disease stage.MethodSubtype and Stage Inference (SuStaIn) is an unsupervised learning technique that combines clustering and disease progression modelling to identify subgroups of individuals (subtypes) with distinct progression patterns (stages) from cross‐sectional datasets. We describe the SuStaIn algorithm and recent enhancements and review previous studies using SuStaIn to analyse Alzheimer’s heterogeneity across a range of measures, including lobar and subcortical structural MRI volumes, tau PET, white matter hyperintensities, CSF and cognitive scores. We present new data applying SuStaIn to a more fine‐grained set of structural MRI features than has been used previously, extracting volumes from 34 cortical regions. 631 amyloid‐positive individuals based on PET or CSF at their most recent visit were selected from the ADNI dataset. 153 amyloid‐negative cognitively normal individuals were used as a control population. SuStaIn was used to estimate subtypes with distinct progression patterns, determine the optimal number of subtypes, and to subtype and stage individuals.ResultAcross previous studies SuStaIn identified three‐four subtypes depending on the choice of biomarkers. Across the 34 cortical regions included in this study, SuStaIn identified a hierarchical organisation of subtypes (Figure 1), with the optimal solution consisting of four subtypes (Figure 2): a ‘typical’ subtype (N=116), a ‘temporo‐parietal subtype’ (N=100), a ‘fronto‐temporo‐parietal’ subtype (N=66) and a ‘frontal’ subtype (N=19). We observed differences between the subtypes in age and number of APOE4 alleles (Table 1). Individuals assigned to the typical and frontal subtypes were older (p<0.001 typical; p<0.05 frontal), and individuals assigned to the temporo‐parietal and fronto‐temporo‐parietal subtypes were younger (p<0.001 temporo‐parietal; p<0.001 fronto‐temporo‐parietal). The temporo‐parietal subtype had the greatest number of APOE4 alleles (p<0.001), whilst the fronto‐temporo‐parietal subtype had the least number (p<0.05), potentially reflecting an atypical Alzheimer’s subtype. The subtype and stage assignments were longitudinally consistent (Figure 3).ConclusionOur results highlight the substantial heterogeneity of Alzheimer’s disease and demonstrate the utility of SuStaIn for identifying Alzheimer’s subgroups and their relationship with demographics, genetics, and cognition.
Clinical Implications of Internal Carotid Arterial Tortuosity in Patients with White Matter Hyperintensities
Authors: Sun Zhe , Li Chenyang , Muccio Marco , Masurkar Arjun V , Wisniewski Thomas , Ge Yulin 
Published: December 2022

AbstractBackgroundWhite matter hyperintensities (WMHs) are observed frequently on MRI in elderly and associated with cognitive dysfunction. Many studies focused on intracranial small vessel disease (SVD), however, few studies linked WMHs with changes of extracranial large feeding arteries. We aimed to investigate the effects of internal carotid artery (ICA) tortuosity changes through quantitative MR Angiography.MethodFifty‐seven patients (age: 72.98±5.62; 32 females/25 males) with WMHs were included. WMHs lesions were semi‐automatically segmented on FLAIR images. ICAs were segmented on the TOF images to generate tortuosity quantitative metrics, including tortuosity index (TI), inflection count metric (ICM), and ICA angle (Figure 1). According to the Fazekas scores, patients were categorized into mild, moderate and severe groups as summarized in Table 1. One‐way ANOVA analyses were applied to reveal the difference of averaged bilateral ICAs' tortuosity measurements. Pearson's correlation coefficients were calculated to quantitatively investigate the relationship between tortuosity and volumes of lesions that are apart from the ventricle in subcortical white matter, i.e., deep white matter lesions (DWMLs), as well as the lesions attached with the ventricular system, i.e., periventricular white matter lesions (PVWMLs).ResultPatients with higher Fazekas scores have higher TI and ICM, indicating higher tortuosity (Figure 2). The correlation results showed that TI and ICM were positively correlated with DWMLs volumes (r = 0.33, P< 0.05; r = 0.4, P< 0.01), however, they did not show associations with PVWMLs. While there's no correlation between averaged bilateral ICA angles and DWMLs or PVWMLs, we found significant correlations between left ICA angles and DWML volumes on left brain (r =0.56, P < 0.005) as well as between right ICA angles and DWML volumes on right brain (r = 0.49, P < 0.05) (Figure 3).ConclusionTortuosity measurements derived from TOF images showed that subjects with higher degree of ICA tortuosity had higher lesion volumes of DWMLs not PVWMLs, indicating DWMLs may have different etiologies such as ischemic origin. The findings also highlight the importance of ICA angle as a risk factor for WMHs development which might be associated with the local hemodynamic shear stress at the bulb, where the ICA plaques are often developed.
Sema6D Promotes TREM2‐dependent Phagocytosis in Human iPSC‐derived Microglia
Authors: Finan Gina M. , Kwak Chulhwan , Hyun‐Woo Rhee , Kim Tae‐Wan 
Published: December 2022

AbstractBackgroundMicroglia mediate key functions in inflammation and phagocytic clearance central to Alzheimer’s disease (AD). Semaphorins and their receptors, plexins and neuropilins, are best known for their role in axon guidance, but emerging roles include the regulation of innate immunity. Semaphorin receptors are highly expressed in microglia, including those encoded by AD risk genes discovered through genome‐wide association studies (e.g. PLXNA4 and PLCγ2). We investigate the function of semaphorin 6D (Sema6D) and interacting receptors in human iPSC‐derived microglia (iMG).MethodWe generated TREM2 knockout (KO) human iPSCs using CRISPR/Cas9. Following differentiation to iMG, we used a proximity labeling approach to demonstrate the interaction of known Sema6D receptors (Plexin‐A1 or Plexin‐A4) with TREM2. WT and KO cells were treated with Sema6D to assay (i) phagocytosis activity via live‐cell imaging and (ii) secretion of inflammatory cytokines via multiplex immunoassays (iii) downstream signaling events.ResultWe demonstrated that Sema6D promotes phagocytic uptake of oligomeric Aβ, and human synaptosomes, as well as significantly increases secretion of several inflammatory cytokines including IL‐1β, IL‐6, TNF‐α and IL‐8. TREM2 KO abrogates Sema6D‐induced cellular changes in iMG. Plexin‐A1 and Plexin‐A4 interact with TREM2 in the intact cell.ConclusionSema6D is a novel ligand for microglial Plexin‐A1and Plexin‐A4 and likely mediates signaling via a co‐receptor complex harboring TREM2. Sema6D is a regulator of microglial phagocytosis and cytokine release in a TREM2‐dependent manner, suggesting a Sema6D‐Plexin/TREM2 pathway as a novel therapeutic target for AD.
Alzheimer’s Disease Preclinical Efficacy Database (AlzPED): Optimizing the Scientific Rigor and Reproducibility of Preclinical Research in Alzheimer’s Disease
Authors: Chakroborty Shreaya , Martin Zane , Yuan Jean , Petanceska Suzana S , Refolo Lorenzo M 
Published: December 2022

AbstractBackgroundAssessments of preclinical animal studies in Alzheimer’s disease (AD) highlight the lack of methodological rigor and inadequate reporting practices as contributive to the preclinical to clinical translation gap in AD therapy development. The Alzheimer’s Disease Preclinical Efficacy Database (AlzPED), a searchable and publicly available knowledgebase developed by the National Institute on Aging aims to illuminate key elements of experimental design and reporting practices of preclinical efficacy testing studies for researchers, funding agencies, and the public. The database is missioned to improve transparency in reporting, increase awareness of the need for greater rigor in study design, and identify critical experimental design elements and methodology missing from studies that make them susceptible to over‐interpretation and reduce their reproducibility and translational value.MethodUsing key word‐driven literature searches published studies are acquired and curated by two experts for bibliographic details, funding source, study goals and principal findings, data on relevant translational criteria like therapy type, therapeutic agent, therapeutic target, animal models, and AD‐related outcome measures, prior to publication in the database. Rigor in study design and methodology is evaluated with a Rigor Report Card consisting of a standardized set of expert‐recommended study design elements.ResultAlzPED hosts curated summaries from nearly 1200 published preclinical therapeutic studies in AD animal models, and data related to 225 therapeutic targets, 1019 therapeutic agents, 195 animal models, more than 2000 AD‐related outcome measures, and thousands of principal findings. Evaluation of Rigor Report Cards from each study demonstrates significant under‐reporting of critical elements of methodology such as power/sample size calculation, blinding, randomization, balancing for sex, animal genetic background, and inclusion/exclusion criteria, these being reported by fewer than 30% of the nearly 1200 curated studies.ConclusionOur analysis of curated studies demonstrates serious deficiencies in reporting critical elements of methodology. These deficiencies diminish the scientific rigor, reproducibility, and translational value of the preclinical studies. Adopting a standardized set of best practices like those proposed by AlzPED can improve the predictive power of preclinical studies in AD animal models and promote the effective translation of preclinical drug testing data to the clinic.