bluuebunny/crossref_metadata_2025_split huggingface dataset:
Novel Wnt modulators for the treatment of Alzheimer’s disease
Authors: Li Yonghe , Caulfield Thomas R. , Macyczko Jesse R , Wang Na , Jia Lin , Shue Francis , Lu Wenyan , Zhao Jing , Martens Yuka A , Liu Chia‐Chen , Bu Guojun 
Published: December 2022

AbstractBackgroundAlzheimer’s disease (AD) is the most common form of age‐related dementia characterized by the presence of amyloid‐β (Aβ) and tau pathologies leading to neurodegeneration and cognitive impairment. Wnt/β‐catenin signaling modulates multiple pathophysiological processes including synaptic plasticity, neuronal survival, neuroinflammation, Aβ production and tau phosphorylation, but this signaling pathway is greatly inhibited in the AD brain. Notably, two SNPs and an alternative splice variant of Wnt co‐receptor LRP6, which result in down‐regulation of Wnt/β‐catenin signaling, are associated with increased risk of developing AD. In addition, apoE4, the strongest risk factor of late‐onset AD, interacts with and decreases cell surface abundance of LRP6 in astrocytes. Studies from our laboratory have demonstrated that the level of LRP6 is significantly downregulated in human AD brains, and that deficiency in LRP6‐mediated Wnt/β‐catenin signaling leads to synaptic abnormalities and amyloid pathology in amyloid model mice. Therefore, LRP6 is an attractive therapeutic target for restoring Wnt/β‐catenin signaling in the AD brain.MethodIn our previous studies, we have discovered niclosamide, an FDA‐approved anthelminthic drug, inhibits Wnt/β‐catenin signaling via promoting LRP6 degradation. Herein, we demonstrated that CI‐994, an analog of niclosamide, exhibits opposite effects on LRP6 level and Wnt/β‐catenin signaling. Following structural optimization, we have generated a series of novel potent Wnt modulators.ResultThe leading compound W2A‐16 displays a good pharmacokinetic profile with high oral bioavailability and brain penetration. Importantly, W2A‐16 significantly activates Wnt/β‐catenin signaling and inhibits tau phosphorylation in AD patient‐specific iPSC‐derived cerebral organoids. Moreover, W2A‐16 attenuates amyloid pathology and gliosis and improves cognitive function in 5xFAD amyloid model mice. Further, W2A‐16 suppresses tau phosphorylation and neuroinflammation, attenuates body weight loss, and improves the survival of PS19 tauopathy mice.ConclusionTogether, these findings demonstrate that W2A‐16 is a strong drug candidate for AD therapy.
Unique brain iron profiles associated with logopenic progressive aphasia and posterior cortical atrophy
Authors: Singh Neha Atulkumar , Arani Arvin , Graff‐Radford Jonathan , Senjem Matthew L. , Martin Peter R , Schwarz Christopher G. , Shu Yunhong , Cogswell Petrice M , Knopman David S. , Petersen Ronald C. , Lowe Val J. , Jack Clifford R. , Josephs Keith A , Whitwell Jennifer L 
Published: December 2022

AbstractBackgroundQuantitative susceptibility mapping (QSM) can detect iron distribution in the brain by estimating the local tissue magnetic susceptibility of every voxel. Dysregulation of neuronal iron has been correlated with typical Alzheimer’s disease (tAD), but little is known about iron distribution in atypical clinical presentations of AD such as logopenic progressive aphasia (LPA) and posterior cortical atrophy (PCA).MethodEleven PCA patients and eight LPA patients were recruited by the Neurodegenerative Research Group at Mayo Clinic, Rochester, MN, and underwent MRI that included a five‐echo gradient echo sequence for calculation of QSM. Mean QSM signal was extracted from gray and white matter for regions‐of‐interest across the brain using the Mayo Clinic Adult Lifespan Template. Hierarchical models were fit per‐region and per‐hemisphere to compare PCA and LPA to each other, to 20 healthy controls, and to 20 patients with tAD recruited by the Alzheimer’s Disease Research Center.ResultStrong evidence (posterior probability>0.99) was observed for greater susceptibility in the left middle occipital gyrus and amygdala in both LPA and PCA, and in the right precuneus and inferior temporal gyrus in PCA compared to controls. Moderate evidence for greater susceptibility (posterior probability>0.90) was also observed in the left insula, inferior occipital gyrus, entorhinal cortex, and right inferior parietal gyrus and amygdala in both LPA and PCA, along with right angular gyrus and middle occipital gyrus in PCA and right insula and caudate in LPA, when compared to controls. Comparing between phenotypes, LPA showed moderate evidence for greater susceptibility in the caudate, hippocampus, substantia nigra, left supramarginal gyrus and posterior cingulate compared to PCA, while PCA showed greater susceptibility in the right precuneus compared to LPA. Both LPA and PCA showed moderate‐strong evidence for greater susceptibility than tAD, particularly in medial and lateral parietal regions.ConclusionUnique iron profiles were identified in LPA and PCA within cortical and subcortical structures. These changes are in line with disease‐related neurodegenerative changes in the clinical phenotypes, suggesting that QSM could be an informative marker to study iron deposition in these patients.
MRI‐guided Clustering of Alzheimer’s Disease patients: A post‐hoc analysis of Phase 3 Trial of Solanezumab for Mild Dementia Due to Alzheimer’s Disease
Authors: Petersen Kellen K. , Lipton Richard B. , Grober Ellen , Nallapu Bhargav Teja , Ezzati Ali 
Published: December 2022

AbstractBackgroundAlzheimer’s disease (AD) is a phenotypically and pathologically heterogenous disorder. We used MRI in amyloid positive patients enrolled in the placebo arm of the Phase 3 Trial of solanezumab for mild dementia due to AD (EXPEDITION3) to identify more homogeneous subgroups based on variation in volumetrics.MethodsWe implemented the self‐organizing map algorithm on baseline volumetric MRI measures from nine brain regions of interest (ROIs) to cluster 1041 individuals enrolled in the placebo arm of the EXPEDITION3 trial. Volumetric MRI differences were compared among clusters. Demographics as well as baseline and longitudinal cognitive performance metrics were used to evaluate cluster characteristics.ResultsThree distinct clusters, with an overall silhouette coefficient of 0.383, were identified based on MRI volumetrics. Cluster 1 (N=400) had the largest baseline volumetric measures across all ROIs and the best cognitive performance at baseline (Table 1). Cluster 2 (N=269) had larger hippocampal and medial temporal lobe volumes, but smaller parietal lobe volumes in comparison with the third cluster (N=372) (Figure 1). Spider plots show the normalized test performance at baseline and follow‐up with larger values corresponding to worse test performance; Cluster 1 shows relatively little cognitive change (Figure 2). Spider plots of regional MRI volumes show smaller volumes for Clusters 2 and 3 relative to Cluster 1 and asymmetries that reflect regional differences in atrophy (Figure 2). The mean change from baseline to week 80 in the ADAS‐cog14 score for Clusters 1, 2, and 3 were 4.28 (SE=0.35), 10.14 (SE=0.51), and 7.90 (SE=0.43), respectively. Significant between‐group mean differences were observed between Clusters 1 and 2 (difference, 2.38; 95% CI, 1.85 to 2.91; P<0.001), Clusters 1 and 3 (difference, 1.93; 95% CI, 1.41 to 2.44; P<0.001), but not between Clusters 2 and 3 (difference, 0.45; 95% CI, ‐0.11 to 1.02; P=0.146) in ADAS‐cog14 (Figure 3).ConclusionsVolumetric MRI can be used to identify homogenous clusters of amyloid positive individuals with mild dementia. The groups identified differ in baseline and longitudinal characteristics. Cluster 1 shows little ADAS‐cog14 change over the first 40 weeks of study on placebo treatment and may be unsuitable for identifying early benefits of treatment.
In Vivo Head‐To‐Head Comparison of [18F]GTP1 and [18F]PI2620 in Alzheimer’s Disease
Authors: Bohorquez Sandra Sanabria , Constantinescu Cristian , Manser Paul T , Gunn Roger N , Russell David S , Tonietto Matteo , Bullich Santiago , Stephens Andrew W , Mueller Andre , Klein Gregory , Teng Edmond , Pickthorn Karen 
Published: December 2022

AbstractBackgroundSeveral radiotracers targeting tau pathology in Alzheimer’s disease (AD) are being used in human studies. Although abundant imaging characterization data exist for individual tracers there are only sparse in vivo data directly comparing tracers in head‐to‐head studies. As the use of tau PET increases, it is of paramount importance to enable multi‐tracer, multi‐center, multi‐national observational and therapeutic trials. We present the direct in vivo comparison of [18F]GTP1 and [18F]PI2620.MethodsTo date, 21 subjects (70±6 years; 12F) have completed imaging with both [18F]GTP1 and [18F]PI2620: 10 prodromal, 9 mild, one moderate AD subjects (Aβ+), and one Aβ‐ cognitively unimpaired subject. Thirty minutes images were acquired 60 and 45 min after [18F]GTP1 and [18F]PI2620 administration, respectively. SUVR was calculated using the inferior cerebellum and used to compare tau‐specific binding and off‐target signal characteristics between the two tracers. The choroid plexus was defined manually for each subject. The whole cortical gray (WCG) and cerebellum rims were defined using the gray and white‐matter SPM tissue segmentation images (Figure 1).ResultsTracer distribution was similar for both tracers (Figures 2 and 3). Hammer atlas cortical SUVRs were linearly correlated (r2=0.88). Higher cortical [18F]PI2620 SUVR were observed in some subjects and regions (Figure 3). A lower SUVR correlation was observed in subcortical regions (r2=0.57). Regional comparisons are shown in Figure 4.ConclusionsThe tau pathology distribution was similar for both tracers although each tracer presents a distinct off‐target signal pattern. These preliminary results support the development of categorical and standardized quantification scales for using both tracers in future studies and bridging existing data sets.Figure 1. Delineation of cortex and cerebellum rims. The combined gray and white matter SPM segmentations were binarized and the ventricles and internal CSF spaces filled to create a mask.Figure 2. [18F]GTP1 and [18F]PI2620 SUVR images.Figure 3. [18F]GTP1 and [18F]PI2620 SUVR in WCG and in vivo Braak regions.Figure 4: [18F]GTP1 and [18F]PI2620 SUVR correlation in target cortical regions, and off‐target signal in choroid plexus (CP), WCG and cerebellum (CBL) rims, and subcortical structures (CAU: caudate; PUT: putamen; PAL: pallidum; THA: thalamus; NAc: nucleus accumbens; SN: substantia nigra) and centrum semiovale (WM).
Bio‐Hermes: A Validation Study to Assess a Meaningful Relationship Between Blood and Digital Biomarkers with Aβ PET Scans for Alzheimer’s Disease
Authors: Beauregard Douglas W. , Mohs Richard , Dwyer John , Hollingshead Sarah , Smith Katy , Bork Jason , Kerwin Diana R. 
Published: December 2022

AbstractBackgroundThe Global Alzheimer’s Platform Foundation® (GAP) has developed a biomarker study (Bio‐Hermes) that will compare results of blood and digital biomarker tests with the results of brain amyloid PET scans and traditional cognitive tests. The trial will enroll 1,000 participants across three cohorts: Healthy, MCI, and Mild AD. In addition, Bio‐Hermes has a discrete recruiting endpoint that requires enrollment of a minimum of 200 participants (20%) from traditionally underrepresented populations (Black/African American & Latino). Bio‐Hermes will generate a unique, well‐characterized, diverse sample set that will explore the utility of several leading biomarkers. This study will contribute to reducing the time and variability of therapeutic clinical trials in Alzheimer’s disease. Bio‐Hermes will generate a first of its kind, “head‐to‐head” comparison of a broad set of AD biomarkers.Method1. GAP activated 13 sites based on high productivity, access to a large AD population, commitment to recruiting traditionally underrepresented populations, and proof of COVID‐appropriate processes and SOPs.2. 3 cohorts established:• Cohort 1 – Healthy• Cohort 2 – MCI verified• Cohort 3 – Mild AD verified3. Sites collect Aß 42/40, p‐Tau 181/217/231, NfL blood biomarkers, full gene sequencing, including APOE status, traditional cognitive tests, family history, medications, retinal scan, digital cognitive tests, and centrally read Aß PET scans.4. Novel and focused recruitment efforts deployed to prioritize diverse representation.ResultAs of 1/27/2022:1. 6% of enrollment goal achieved (686 out of 1,000)• Cohort 1: 371 enrolled out of 400, (21% Aß Positive)• Cohort 2: 244 enrolled out of 300, (34% Aß Positive)• Cohort 3: 71 enrolled out of 300, (55% Aß Positive)2. 19% from traditionally underrepresented populations3. Screen fail rate of 15.9%4. 208 participants enrolled in the Retispec Sub‐StudyConclusionBio‐Hermes provides a well‐characterized, highly useful dataset including one of the most diversified populations in an AD study, illustrating that traditionally underrepresented populations can be successfully recruited. This study facilitates the discovery of potential biomarkers when compared to Aß PET and validates their predictive value for assessment/screening purposes. Bio‐Hermes is establishing a subset of potential participants for downstream AD therapeutic trials that will significantly lower screen fail rates.
Visualization of synaptic vesicle protein 2A in a rodent model of familial Alzheimer’s disease with a metabolically stable PET probe
Authors: Zheng Chao , Chen Baosheng , Toyonaga Takuya , Liu Michael , Nicholson LaShae , Deluca Kristin , Strittmatter Stephen M , Carson Richard E. , Huang Yiyun , Cai Zhengxin 
Published: December 2022

AbstractBackgroundSynaptic loss is one of the hallmarks of Alzheimer’s disease (AD) and region‐specific changes in synaptic density is associated with a variety of neuropsychiatric diseases. Here, we investigated the expression levels of synaptic vesicle glycoprotein 2A (SV2A) in APP/PS1 and age‐matched wild‐type (WT) mice using [18F]SDM16, a novel, metabolically stable SV2A PET imaging probe.MethodsThe SV2A tracer [18F]SDM‐16 was synthesized according to previously published procedure [1]. PET scans with [18F]SDM‐16 were performed on a Focus‐220 scanner in APP/PS1 transgenic mice and WT controls. Regions of interest (ROIs) were extracted from the Ma‐Benveniste‐Mirrione mouse brain atlas and regional time‐activity curves (TACs) were obtained by applying template ROIs to the averaged PET images from 0‐90 min post‐injection (p.i.). Distribution volume ratio (DVR) values were generated using the simplified reference tissue model (SRTM), with brain stem as the reference region. Averaged SUV ratios (SUVRs) from 60‐90 min were calculated by using brain stem as reference region. Spatially normalized SUVR(BS) were assessed on a voxel‐by‐voxel basis in Matlab R2018 with Statistical Parametric Mapping.ResultsThe mouse brain PET images showed ubiquitous uptake of [18F]SDM‐16. Regional TACs showed high brain uptake in the selected brain regions of mice (SUV up to 2.38), with a steady increase after tracer injection, before plateauing at 60‐90 min p.i. (Fig. 1a). DVR results correlated well with SUVR(BS) from 60‐90 min (R2 = 0.94, p < 0.0001). Compared with age‐matched WT controls, the averaged SUVR(BS) in the whole brain and hippocampus of APP/PS1 mice showed statistically significant lower values by 5.4% (p = 0.01) and 11% (p = 0.001), respectively (Fig. 1b). These results are consistent with those from previous reports using [11C]UCB‐J (4.0% decrease in hippocampus) and [18F]SynVesT‐1 (7.5% decrease in hippocampus) [2, 3]. Voxel‐based parametric analysis also showed a global decrease in tracer uptake in the APP/PS1 mice, with the most significant decrease in the hippocampus, which is consistent with the results from ROI‐based analysis.ConclusionsWe demonstrated that the radioligand [18F]SDM‐16 had high uptake in mouse brain, and APP/PS1 mice showed lower tracer uptake than WT mice, supporting the use of [18F]SDM‐16 in preclinical AD drug discovery and development.
APOE2 is associated with amyloid independent effects on tau PET signal in preclinical AD
Authors: Young Christina B , Kennedy Gabriel , Sperling Reisa A. , Buckley Rachel F. , Insel Philip S. , Greicius Michael D , Poston Kathleen L , Mormino Elizabeth C. 
Published: December 2022

AbstractBackgroundAlthough APOE is strongly associated with risk of amyloid‐positivity during the preclinical stage of AD, less is known regarding independent effects on regional tau PET burden.MethodWe examined 385 Amyloid‐positive (A+) clinically unimpaired (CU) individuals that had APOE genotype available and additionally underwent amyloid (florbetapir) and tau (flortaucipir) PET imaging as part of the A4‐LEARN study (Table 1A, mean age=72.1±4.8). PET data were processed locally using FreeSurfer defined regions to quantify regional tau and combined to form a large cortical target composite for amyloid. Multiple regression was used to examine associations between APOE genotype (number of e2 and number of e4 modeled as two predictors) with global amyloid, regional tau (entorhinal, amygdala, and inferior temporal).ResultAmong the A+ group, each APOE2 allele was associated with a decrease of 0.045 SUVR while each APOE4 allele was associated with an increase of 0.068 SUVR units of global amyloid compared to the APOE3/3 group (Table 1B). APOE2 was significantly associated with reduced tau across medial temporal lobe ROIs whereas APOE4 was associated with elevated tau in the medial temporal lobe ROIs (Table 1B, Figure 1). Although continuous amyloid levels were associated both with APOE genotype, the total effect of both APOE2 and APOE4 dosage on tau PET was largely independent of continuous amyloid levels (Figure 2).ConclusionAPOE genotype is related to early medial temporal lobe tau burden, independent of continuous amyloid burden within the A+ range. These findings highlight that APOE genotype influences heterogeneity in tau burden among individuals with preclinical AD.
Plasma amyloid β 42/40 associations on episodic memory: Moderations with depressive symptoms and marital status
Authors: So Mae Yue , Erickson Kelsey , Farias Sarah Tomaszewski , Olichney John M. , Jin Lee‐Way , DeCarli Charles S. , Sapkota Shraddha 
Published: December 2022

AbstractBackgroundPlasma amyloid β (aβ) 42/40 is a non‐invasive and cost‐effective biomarker associated with aβ accumulation and cognitive performance in normal aging and Alzheimer’s disease. Recent studies have linked plasma aβ 42/40 to well established modifiable risk factors for dementia. Specifically, depressive symptoms (DS) and marital status have been associated with steeper cognitive decline and increased dementia onset. We examine whether the association between plasma aβ 42/40 and episodic memory (EM) is moderated by (1) DS, (2) marital status, and (3) additive risk of DS+ marital status.MethodWe used an ethnically and clinically diverse longitudinal cohort of older adults (n=473, mean baseline age=74.81(7.22) years, 60.5% women) from University of California, Davis‐Alzheimer’s Disease Research Center (Table 1). Statistical analyses included latent growth modeling to establish a latent EM growth model, and regression analyses to test independent associations and moderations with DS (measured with Geriatric Depression Scale; low<5/ high≥5), marital status (married/not married), and combined DS+marital status risk (low: low DS+married/intermediate: high DS+married or low DS+not married/high: high DS+not married). Age was centered at 75 years. Sex and education were included as covariates.ResultLower aβ42/40 was associated with lower EM performance and steeper decline (level: β=6.195, SE=3.065, p=0.041, slope: β=0.284, SE=0.134, p=0.034). DS and marital status independently moderated this association. Specifically, lower aβ42/40 was associated with (1) poorer EM performance in the high DS groups (n=80; level: β=8.914, SE=4.353, p=0.014) and (2) poorer EM performance and steeper decline in the married group (n=115; level: β=11.157, SE=4.477, p=0.013, slope: β=0.524, SE=0.219, p=0.017). The effects of these independent associations were magnified with combined DS + marital status. Specifically, lower aβ42/40 was associated with poorer EM performance and steeper decline in the low (n=62; level: β=15.445, SE=5.650, p=0.006, slope: β=0.642, SE=0.305, p=0.035) risk group but this association was absent in the intermediate (n=171) and high (n=56) groups.ConclusionThe impact of amyloidosis, as measured by plasma aβ42/40 on cognition, may be more prominent in married older adults with low DS. Examining multimodal associations of non‐invasive plasma biomarkers with modifiable risk factors may identify older adults with high cognitive decline and dementia risk profiles.
THE GLUTAMATERGIC SYSTEM IN ALZHEIMER’S DISEASE: A SYSTEMATIC REVIEW WITH META‐ANALYSIS
Authors: Soares Carolina , das Ros Lucas U. , da Rocha Andreia Silva , Machado Luiza Santos , Bellaver Bruna , Zimmer Eduardo R. 
Published: December 2022

AbstractBackgroundGlutamate is the most important excitatory neurotransmitter in the human brain, and the regulation of its homeostasis is of utmost importance for brain proper functioning. At the synapse level, glutamate binds to ionotropic (NMDAR, AMPAR and KAR) and metabotropic receptors (8 isoforms, mGluR1 to mGluR8). Also located at the glutamatergic synapse are the vesicular transporters (vGLUT), a synaptic marker, and glutamate transporters (GLT1), which are responsible for glutamate re‐uptake. Increases in the glutamate concentration in the synaptic cleft leads to a phenomenon called excitotoxicity, which causes progressive neuronal death. Nonetheless, glutamate excitotoxicity has been described as a common feature in neurodegenerative disorders, including Alzheimer’s Disease (AD). Multiple studies reported alterations in the glutamatergic system in the AD brain. Thus, considering the large number of publications, we sought to perform a systematic review with meta‐analysis to assess whether the glutamatergic system is consistently altered in AD patients.MethodPubMed and Web of Science databases were searched for articles that evaluated glutamatergic system components in AD. Pooled effect sizes were determined with standardized mean differences using the Hedge G method with random effects.ResultThe search initially retrieved 6000 articles. Following exclusion criteria, 59 articles were included in this study. We found that regions typically affected with AD pathology presented reduced NMDAR subunit NR1 (p = 0.017, z = 2.38, i2 = 71.3%) (Figure 1), NR2A (p = 0.001, z = 3.38, i2 = 0%) (Figure 2), NR2B (p < 0.0001, z = 3.86, i2 = 0%) (Figure 3), AMPAR subunits GluA2/3 (p = 0.018, z = 2.36, i2 = 84.5%) (Figure 4). Conversely, we did not observe significant differences in the level of GLT1, vGLUT1, vGLUT2, AMPAR subunit GluA1 and mGluRs in postmortem brain tissue. Further analyses are in process to assess other glutamatergic components, as well sensitivity analysis considering risk of bias for each study.ConclusionIn conclusion, the early results of this meta‐analysis suggest that changes in the glutamatergic system in AD are not generalized, but specifically related to ionotropic receptors.