bluuebunny/crossref_metadata_2025_split huggingface dataset:
The induction of the mitochondrial morphofunctional pathways improves bioenergetics in Alzheimer Disease
Authors: Nguyen Thi Kim Oanh 
Published: December 2022

AbstractBackgroundAlzheimer Disease (AD) currently has no effective treatments. A consistent failure of recent clinical trials focused on Aβ or pTau protein accumulation necessitates the identification of novel therapeutic targets and strategies. The loss of cellular energetics is considered as an underlying dysfunction in AD. We have identified small molecule compounds that partially inhibit mitochondrial complex I (MCI), blocking neurodegeneration via the induction of multiple neuroprotective mechanisms, including the improvement of cellular energy homeostasis in vitro and in vivo in multiple AD models. Mitochondria are highly motile organelles that respond to physiologic cues through the dynamic properties of mitochondrial networks, which are balanced by the flux of fusion and fission events. This study aims to demonstrate that treatment with partial MCI inhibitors improves cellular energetics and function via modulation of mitochondrial dynamics using multiple models, including neuronal cells generated from human iPSCs derived from ApoE4+ late‐onset AD (LOAD) patients and ApoE3+ controls.MethodChanges in protein expression in response to treatment were assessed using the Western Blot analysis. The investigation of mitochondrial morphology was done using electron microscopy. Flow cytometry was used to measure the translocation of glucose transporters to the cell surface. Cellular energetics was assessed using a Seahorse Extracellular Flux Analyzer. Results were validated in 3xTgAD mice.ResultWe found that the 2D culture of LOAD cultures had accumulation of pTau and a significant reduction in the expression of proteins involved in mitochondrial dynamics and function, including mitochondrial preprotein translocase TIM23, mitochondrial transcription factor A, transcription factor FoxO3, and mitochondrial fusion proteins MFN2 and OPA1. Treatment with partial MCI inhibitors improved mitochondrial dynamics, rescuing the expression of MFN2 and OPA1, neuronal bioenergetics, and mitochondrial morphology. MCI inhibitors increased surface translocation of GLUTs enhancing glucose uptake and utilization, which could be measured in 3xTgAD mice in vivo using translational biomarker FDG‐PET.ConclusionMild stress caused by the application of MCI inhibitors induced mitochondrial fusion, improved energy homeostasis, and enhanced glucose uptake and utilization in vitro and in vivo. These findings could be instrumental for the validation of a novel medicinal approach and the development of biomarkers for therapeutic efficacy.
Differential vulnerability of hippocampal microstructure in 5xFAD mouse model of Alzheimer’s Disease: A dMRI study
Authors: Shahid Syed Salman , Lamb Bruce T , Oblak Adrian L , Wu Yu‐Chien 
Published: December 2022

AbstractBackgroundHippocampal subfields exhibit differential vulnerabilities to Alzheimer’s disease (AD) associated pathologies. These pathological processes extensively attenuate the structural and functional interconnectivities of the subfields. Abnormal accumulation of beta‐amyloid (Aβ) is considered a primary hallmark of AD. Histopathological studies suggest region‐specific accumulation of Aβ in hippocampal subfields. The aim of the current study is to understand the subfield‐specific in‐vivo microstructural changes in hippocampus due to Aβ load in 2.5 months old 5xFAD mouse model of AD.MethodTwo and a half month old male 5xFAD and age‐matched littermate controls were used in this study. DWI and anatomical images were acquired on a horizontal bore 9.4T Biospec micro‐MRI system equipped with a H1 cryogenic surface coil. 2D T2‐weighted anatomical images were acquired using the following parameters: TE/TR=43.67/7500 ms, voxel size=117x117x250 µm3 and number of slices=20. DWIs were acquired using multi‐shot dual‐spin‐echo EPI sequence using following parameters: TE/TR=34.78/3000 ms, voxel size=117x117x250 µm3, number of slices=20, 3 b‐values (650, 1200 and 2500) s/mm2, 5 b0 per shell, 12 diffusion encoding direction for b=650, 60 for b=1200 and 80 for b=2500 s/mm2. T2‐W images were nonlinearly registered to Badhwar hippocampal atlas. Hippocampal subfields (CA1, CA2, CA3, DG and Subiculum) in atlas space were transformed to individual T2W space and then linearly transformed to DWI space. Multi‐compartment microstructural imaging was performed using Cortical‐NODDI. Volume fraction of isotropic water diffusivity (VFISO) and intracellular volume fraction (VFIC) maps were calculated. The regional mean values (VFIC and VFISO) of individual subfields were extracted and used in general linear model for group‐comparisons.ResultThe results of the study suggest group‐level differences between control and 5xFAD mice in cornu ammonis regions. Compared to 5xFAD, VFIC in littermate control mice was significantly higher in CA1 (p<0.05; d=1.47), CA2 (p<0.05; d=1.11) and CA3 (p<0.05; d=1.54). VFISO in DG was significantly lower in littermate control compared to 5xFAD mice (p<0.05; d=1.31).ConclusionThe study demonstrates the importance of utilizing tissue‐specific microstructural imaging in detecting Aβ associated microstructural alterations in multiple hippocampal subfields. This study demonstrates that Aβ alters the hippocampal microstructure. study also suggests on the differential effect of Aβ pathology on hippocampal microstructure.
Functional connectivity of basal nucleus of Meynert, locus coeruleus and ventral tegmental area in MCI and mild dementia in Alzheimer’s disease
Authors: Burle Fernanda , Guimaraes Santos , Balthazar Marcio Luiz Figueredo , de Campos Brunno 
Published: December 2022

AbstractBackgroundCholinergic, noradrenergic and dopaminergic dysfunction plays an important role in Alzheimer’s disease (AD). Basal nucleus of Meynert (BNM), locus coeruleus (LC) and ventral tegmental area (VTA) are its main producer nuclei, respectively. Neuropathological studies have shown that structural changes are present in these areas from the beginning of the disease. As such, we aim to identify changes in the functional connectivity (FC) from these nuclei in patients with mild cognitive impairment (MCI) and dementia (DA) in AD, compared with healthy controls (HCs).MethodWe analyzed data from 43 subjects with altered beta‐amyloide in the cerebrospinal fluid (23 MCI; 20 mild to moderate dementia) and 16 controls. Participants underwent rs‐fMRI and neuropsychological evaluation. FC maps to the whole brain were generated (UF²C‐toolbox) using the BNM, LC and the VTA as seeds separately. The second level analysis was performed with an ANCOVA test including the individual FC maps, transformed to z‐score (Fischer R‐Z transformation) generated with each seed and group and regressing for age and years of education using SPM12‐toolbox. The significance level was defined as p<0.001 at the voxel level and p<0.05 FDR corrected at the cluster‐level. In addition, only anatomical regions with more than 60 voxels were described.ResultRegarding BNM, compared to HCs, patients with MCI showed significantly decreased FC in the left precentral gyrus and left anterior insula (volume 62.05 and 61.59 voxels, respectively, Figure 1). Similarly, DA patients, when compared to HCs, showed significantly decreased FC in the left and right medial precentral gyrus (volume 104.06 and 82.75 voxels, respectively) and in the right supramarginal gyrus (volume 64.68 voxels, Figure 2). Regarding VTA, unexpectedly, we found that, compared with MCIs, DA patients showed increased FC in the left central operculum (volume 92.29 voxels, Figure 3). There were no other between‐group changes that reached statistical significance for right and LC and VTA.ConclusionAD patients present changes in the NBM‐FC to the precentral gyrus, insula and supramarginal gyrus. These findings may embase new research for cholinergic dysfunction and possible biomarkers.
Predicting neurodegenerative disease using the unique gut microbiota composition of transgenic mice modeling amyloid‐β plaques and neurofibrillary tangles
Authors: Borsom Emily M , Conn Kathryn A , Keefe Christopher R , Hirsch Allyson H , Orsini Gabrielle M , Jaramillo Sierra A , Testo George , Avila Melanie Palma , Bolyen Evan K , Dillon Matthew R , Lee Keehoon , Caporaso J. Gregory , Cope Emily K 
Published: December 2022

AbstractBackgroundThe gut microbiota, the aggregates of microbial cells that inhabit the gastrointestinal tract, communicates bidirectionally with the brain via immune, neural, metabolic, and endocrine pathways, known as the gut‐brain axis. The gut‐brain axis is suspected to contribute to the development of Alzheimer’s disease (AD). We hypothesize that altered gut microbiota composition contributes to the development of AD pathologies and neuroinflammation via the gut‐brain axis.MethodTo characterize the gut microbiota of 3xTg‐AD mice modeling plaque deposition and hyperphosphorylated tau, fecal samples were collected fortnightly from 4 to 52 weeks of age (n=57 3xTg‐AD mice, n=31 wild‐type). The V4 region of the 16S rRNA gene was amplified and sequenced on the Illumina MiSeq. Data were analyzed using QIIME 2. Targeted reverse transcription qPCR assays were used to assess inflammation in the hippocampus and colon at 8, 24, and 52 weeks of age. Fold change was calculated using ΔΔCt.ResultOur results show altered microbial communities in 3xTg‐AD mice when compared to wild‐type [(PERMANOVA (8 weeks, p=0.001), (24 weeks, p=0.039), (52 weeks, p=0.058)]. Using q2‐longitudinal, we identified a temporal increase in Bacteroides acidifaciens and Turicibacter spp. in 3xTg‐AD mice (r‐squared = 0.658615). Using Random Forest, we successfully predicted strain in 3xTg‐AD mice 100% of the time, and in WT mice 92.85% of the time, improving accuracy over baseline assignment by 1.3 fold. Colonic expression of GFAP was increased at 24 week 3xTg‐AD mice compared to 52 week 3xTg‐AD mice (p=0.009, Mann‐Whitney). Colonic gene expression of IL‐6 was increased in 52 week 3xTg‐AD mice compared to 52 week WT mice (p=0.015, Mann‐Whitney). Hippocampal expression of GFAP was increased at 52 week 3xTg‐AD mice compared to 52 week WT (p=0.049, Mann‐Whitney). Finally, hippocampal expression of Mrc1 was elevated at 24 weeks in 3xTg‐AD mice compared to 52 weeks (p= 0.004, Mann‐Whitney).ConclusionWe have identified changes in the gut microbiota and immune response that may be predictive of the development of AD pathologies. Future shallow shotgun metagenomics sequencing will assess strain‐level features and functions of the gut microbiota in AD.
Effects of Dementia and MCI on Diffusion Tensor Metrics Using the Updated ADNI3 DTI Preprocessing Pipeline
Authors: Thomopoulos Sophia I , Nir Talia M , Reina Julio E Villalon , Zavaliangos‐Petropulu Artemis , Maiti Piyush , Nourollahimoghadam Elnaz , Zheng Hong , Jahanshad Neda , Thompson Paul M 
Published: December 2022

AbstractBackgroundDiffusion magnetic resonance imaging (dMRI) provides insight into white matter (WM) microstructural changes in Alzheimer’s disease and mild cognitive impairment (MCI). The Alzheimer’s Disease Neuroimaging Initiative’s (ADNI) has currently extended its ADNI3 imaging protocol to include dMRI from Siemens, Philips and General Electric (GE) scanners, resulting in seven vendor‐specific dMRI acquisition protocols (Table1). Here we present the updated ADNI3 preprocessing pipeline1 (Figure1) for diffusion tensor imaging (DTI) metrics made available via ADNI’s database, and evaluate their utility for detecting WM differences associated with clinical impairment.MethodRaw dMRI downloaded from ADNI are first denoised using DiPy’s principal component analysis (PCA) denoising algorithms: local PCA for zero‐padded k‐space data (GE), or Marchenko‐Pastur PCA for data with the original acquisition matrix (Siemens/Philips). dMRI are then corrected for Gibbs ringing, eddy currents using FSL’s eddy_cuda with repol outlier estimation and slice‐to‐volume correction, intensity inhomogeneity with ANTS N4, and echo‐planar imaging distortions with a three‐channel non‐linear registration of the subject‐level preprocessed average B0 image to the subject’s skull‐stripped T1‐weighted MRI. Bias field correction is applied again to dMRI with FSL‐FAST. DTI fractional anisotropy (FA), axial, mean and radial diffusivity (AxD, MD, RD) are estimated with FSL’s dtifit, using weighted least squares. The JHU ICBM‐DTI‐81 atlas FA is warped to subject‐level FA maps using ANTS, and the transformations are applied to atlas labels. Subject‐level mean and robust mean (using M‐estimator from R’s ‘WRS2’ package) of DTI metrics within 73 WM regions of interest (ROIs; Table2) are extracted. Here, we fit linear mixed effects models of diagnosis (N=733) and clinical dementia rating (CDR‐sob; N=682; Table3) in 28 of the 73 available ROIs, covarying for age, sex, age*sex, and including nested protocol|site variables as random effects; multiple comparisons were corrected for using false discovery rate (q=0.05).ResultLower anisotropy and greater diffusivity were associated with greater impairment, particularly in the hippocampal cingulum (Figure2). Results from mean and robust mean metrics were comparable. Overall, our results follow previous work2,3 using publicly available ADNI dMRI.ConclusionSubject‐level ADNI3 dMRI measures, sensitive to clinical indices of impairment as presented here, are available at https://ida.loni.usc.edu/.
References: [1 ]Thomopoulos (2021), https://doi.org/10.1117/12.2606337; [2] Nir (2013), https://doi.org/10.1016/j.nicl.2013.07.006; [3] Zavaliangos‐Petropulu (2019), https://doi.org/10.3389/fninf.2019.00002.
Design, test, validate: development of a novel & robust analytic framework and econometric model using administrative claims data
Authors: Soenksen Dirk , Kleinman Nathan 
Published: December 2022

AbstractBackgroundAs health care expenditures continue to rise, policy makers and payers are assessing whether the cost of virtual care programs are justified by their outcomes.Ceresti has developed a novel, robust analytic approach and econometric model to assess the efficacy and overall value of virtual care programs. The methodology uses an administrative claims‐based, analytic and statistical framework that accurately identifies and measures reduction in costs and services (including potential savings from avoiding other costly downstream events) attributable to deployed virtual care programs.MethodThe analytic framework and econometric model were developed for and validated in a pragmatic trial in a Medicare‐aged population.A total of 164 subjects were enrolled in the trial sponsored by a leading Medicare Advantage plan and Ceresti Health. The pragmatic trial compared changes in patient outcomes between program enrollees (DCEP “Care Recipients”) and a matched comparison group using a “difference‐in‐differences” approach.General Matching criteria included:AgeGenderGeographic regionAligned index dates between Care Recipients and the comparison groupDuring the 6 month pre‐index period matching criteria included:Charlson Comorbidity Indexnumber of condition‐specific medical claimspresence of a skilled nursing facility claimemergency department (ED) visits and costsinpatient hospital admissions and costscosts for nursing or assisted living, office visits and other outpatient servicesCosts and service utilization of Care Recipients and the matched comparator group were extracted from an administrative claims database.Total medical and inpatient costs were captured during the pre‐ and post‐index periods for the active and comparator arms. The frequency of ED visits, inpatient admissions, and 30‐day readmissions were calculated per patient per month. The change in costs and visit frequency that Care Recipients incurred > 30 days post‐index to the end of the study was compared to the change experienced by the matched comparator controls.ResultsThe analytic model detected statistically significant pre‐, post‐efficacy across health‐related and economic outcomes.ConclusionThe analytic and statistical framework validated in this trial overcomes the challenge of attributing claims‐based outcomes to virtual care interventions, and contribute to the methods available to accurately measure the value of virtual care programs in Medicare‐aged populations.
Examining the Use and Value of Applied Skills Assessment for the Training of Cognitive Measures in Alzheimer’s Disease (AD) Trials
Authors: Carbo Melissa A , Scalzo Nola , Avrumson Rolana , Komorowsky Andrew , Ogden Kristine 
Published: December 2022

AbstractBackgroundThere are many potential variables that may confound trial results; Sadler, et al. (2017) supported use of Rater Training as an effective method to improve the reliability and accuracy of endpoint measures. Consistent administration and scoring of cognitive assessments are critical to the success of AD trials.MethodThis analysis examines the benefits of implementing an Applied Skills Assessment (ASA) component to standardized Rater Training programs across multiple AD trials. Data was collected from four trials, Phase II and POC, with raters of varying education and experience levels. A detailed review of conceptual knowledge was followed by an Applied Skills Assessment. The ASA required each rater to demonstrate their proficiency with administering a critical cognitive measure for each respective study (such as the Alzheimer’s Disease Assessment Scale‐Cognitive Subscale (ADAS‐Cog), Mini Mental State Examination (MMSE), Hopkins Verbal Learning Test‐Revised (HVLT‐R) and the Severe Impairment Battery (SIB)). Each ASA was evaluated by highly experienced and trained members of a clinical assessment team with immediate feedback delivered.ResultData was acquired from 314 raters of various education and experience levels across eight different countries. Following the detailed conceptual knowledge review, 62% of raters demonstrated errors during the Applied Skills Assessment. There was no notable difference identified across educational degree however there was a dispersion across experience level. It was found that 50% of errors demonstrated were made by raters who reported 0–5 years of Alzheimer’s research experience. Improved performance was observed among raters in the categories of 6–10 years and >10 years of Alzheimer’s Research Experience with a lower rate of error of 22% and 28%, respectively.ConclusionResults support the value in implementing an applied skills exercise to enhance the Rater Training programs for cognitive assessments. Khan (2016) suggests that rater performance tends to significantly improve with re‐training and feedback which applies across various experience levels. A training involving the evaluation of a rater’s applied performance, that includes feedback by a skilled assessor, may prove to be instrumental in contributing to the enrollment of appropriate study participants and achievement of high‐quality reliable endpoint data in Alzheimer’s Disease research.
Hippocampal CA1 volume is associated with higher p‐tau and diminished memory performance in normal older adults
Authors: Tran Tammy T , Trelle Alexandra N , Hunt Madison , Guo Wanjia , Nadiadwala Ayesha , Wilson Edward N. , Deutsch Gayle , Sha Sharon , Andreasson Katrin I. , Carr Valerie A , Kerchner Geoffrey A. , Mormino Elizabeth C. , Wagner Anthony D 
Published: December 2022

AbstractBackgroundPrior work has demonstrated that elevated CSF biomarkers in older adults are associated with diminished performance across several hippocampally‐dependent memory tasks. It is unknown whether early structural changes in medial temporal lobe subfields (1) may be impacted by elevated p‐tau181, and (2) mediate the effect of p‐tau181 on memory performance in older adults.MethodThe current study draws on a cohort of 147 cognitively unimpaired older adults (Stanford Aging and Memory Study) that completed both 3T MRI and lumbar punctures. To examine memory performance, participants completed two hippocampally dependent tasks: a paired associate cued recall task and a mnemonic discrimination task (MST) that examined discrimination between previously studied “old” objects, novel “foil” objects and perceptually similar “lure” objects. Lure trials were binned in five difficulty levels, ranging from low to high similarity compared to previously presented stimuli. Hippocampal subregions (CA1, CA3/DG, subiculum) were manually delineated on T2*weighted images following Carr et al., (2017). CSF was processed with Lumipulse to measure Ab42:Ab40 ratio and p‐tau181. Multiple regression was used to assess the associative memory d’ from the paired associate task. Given the repeated measures design of the MST task, linear mixed models were conducted to understand the association between hippocampal subfields and p‐tau181 on performance as a function of similarity strength (Trelle et al., 2021). Age, sex, and education were controlled in all models.ResultP‐tau181 was correlated with reduced left CA1 volume (partial r2=0.043, p = 0.01), but not with volume in other hippocampal subfields. Increased CA1 volume was positively associated with better memory performance, including higher associative memory recall and old‐lure discrimination. After controlling for p‐tau181, CA1 volume was no longer associated with performance on the associative memory task but remained significantly correlated with old/lure discrimination. Notably, increased CA1 volume improved overall discrimination for old/lure trials, independent of the difficulty level, while the association between p‐tau181 and performance was strongest at the lower similarity level.ConclusionReduced CA1 volume and p‐tau explain unique variance in memory performance in older adults. This combination of biofluid biomarkers and high‐resolution MRI has the potential to understand mechanisms underlying age‐related memory decline.