bluuebunny/crossref_metadata_2025_split huggingface dataset:
A more natural context: Variation in mouse background improves models of vascular contributions to Alzheimer’s disease
Authors: Onos Kristen D , Keezer Kelly J , Uyar Asli , Yang Hongtian Stanley , Carter Gregory W , Territo Paul R , Walker Ashley E , Patel Hemal H , Sasner Michael , Howell Gareth R 
Published: December 2022

AbstractBackgroundInitial research focused on vascular contributions to dementia often categorized these pathologies as not relevant to Alzheimer’s disease (AD). Patients that presented with vascular pathologies would commonly be excluded from clinical studies and trials of AD. Recently, these vascular contributions have become more appreciated. A number of studies have identified vascular factors either contribute to, or result from central AD hallmarks such as amyloid and tau pathology, and glial cell dysregulation. A number of genetic risk factors for AD are also centered on vascular cells and function. Unfortunately, current mouse models are limited in their presentation of vascular pathologies, and require introduction of other interventions such as diet‐induced obesity or middle cerebral artery occlusion.MethodOur group performed a strain survey using amyloid drivers. APP/PS1 transgenes were backcrossed from C57BL/6J to nine strains including wild‐derived WSB/EiJ, PWK/PhJ and CAST/EiJ. All strains were assessed for cerebral amyloid angiopathy (CAA) as this vascular pathology is common in AD cases.ResultWSB/EiJ showed the highest incidence of CAA, accompanied by indications of vascular leakage and damage. Male and female WSB.APP/PS1 and WSB mice were then aged from 4 to 18 months. Amyloid deposits co‐localized with astrocyte processes, but were devoid of microglia and collagen. Brain transcriptional profiling comparing differences between WSB and B6 context identified significant differences in gene expression relating to vascular health including basement membrane, endothelial function and blood vessel formation. Furthermore, upon examination of aged WSB, microbleeds were present even in the absence of amyloid. Single‐cell sequencing of WSB‐microglia states identified a signification proportion of homeostatic microglia enriched for expression of P2ry12 present in WSB but not WSB.APP/PS1. As P2RY12‐mediated chemotaxis is critical for closure of the blood brain barrier (BBB) after injury, these microglia may be central to BBB health in the WSB context. Further work is being performed to determine whether differences in microglia states, vascular integrity or metabolic dysfunction contribute to significant development of CAA present in WSB/EiJ.ConclusionThe WSB genetic context provides a new platform to dissect vascular contributions to AD. Other factors such as humanized amyloid, tau, and apolipoprotein E are also being examined.
Racial Differences in the Association of MIND Diet/Physical Activity Combinations and Cognition in older adults
Authors: Holland Thomas Monroe , Agarwal Puja , Dhana Klodian , Desai Pankaja , Liu Xiaoran , Krueger Kristin R , Beck Todd , Cherian Laurel J , Schneider Julie A , Aggarwal Neelum T. , Barnes Lisa L. , Rajan Kumar B 
Published: December 2022

AbstractBackgroundDiet and physical activity (PA) are important factors associated with improved cognition. Few studies have investigated the synergistic association with cognitive decline and further, whether the association differs by race. In this study, we investigate whether the observed association of high MIND diet score/high self‐reported PA and cognitive decline is different between African Americans (AA’s) and European Americans (EA’s).MethodWe examined the association of baseline MIND diet and PA combinations on cognition in 3,657 participants (2206 AAs and 1451 EAs; mean age = 73.2±SD5.8 years) from the Chicago Health and Aging Project. Diet was assessed using a validated 144‐item food frequency questionnaire; self‐reported PA was measured by frequency of engagement in six activities. Cognition was evaluated using a four‐test cognitive battery from which a global composite score and two domains were derived. Participants were followed on average 8.5±SD4.8 years and separated into 9 combinations of MIND diet score and PA (high, moderate, low for MIND diet and high, moderate, low, for PA). Using linear mixed models we examined the rate of cognitive decline; adjusting for age, sex, education, race, ApoE‐4, smoking, and caloric intake. Subsequent models were stratified by race to investigate potential differences in the association of diet and PA combinations with cognitive decline.ResultParticipants who reported high MIND/high PA had a slower rate of decline in global cognition (β = 0.015, 24.87% slower, p = 0.007), memory score (β = 0.014, 31.86% slower, p = 0.042) and improved MMSE (β = 0.023, 33.62% improvement, p<0.001) when compared to participants with low MIND/low PA. In race stratified models, we found that in European Americans, high MIND/high PA was associated with slower rates of decline in global cognition (β = 0.028, 37.1% slower, p = 0.007), memory score (β = 0.026, 48.59% slower, p = 0.033) and improved MMSE (β = 0.050, 50.0% improvement, p<0.0001) versus low MIND diet/low PA. However, only an improved MMSE (β = 0.017, 27.11% improvement, p = 0.033) was observed to be associated in African Americans.ConclusionHigh adherence to MIND diet/physical activity is associated with slower cognitive decline, regardless of race. However, the breadth of these associations may differ by race. Additional studies are required to elucidate the potential racial differences observed and determine which interventions are most impactful.
Complement C3 Lowering in Adult Inducible Conditional Knockout Mice: Long‐Lasting Effects
Authors: Batista Andre Felipe , Schroeder Maren K , Khan Khyrul , Yalcin Esra , Mei Michelle , Presumey Jessy , Li Shaomin A , Carroll Michael , Lemere Cynthia A. 
Published: December 2022

AbstractBackgroundComplement C3, a central component of the complement cascade, participates in synaptic elimination during brain development and is elevated in the brain with aging and Alzheimer’s disease (AD). Germline C3 knockout (KO) protects against age‐ and AD‐related hippocampal synapse loss and functional decline (Shi Q et al., J Neurosci 2015; Shi Q et al., Sci Transl Med 2017). We crossed C3fl/fl mice with Rosa26‐Cre‐ERT2 mice to generate global C3 inducible conditional KO mice (C3iKO). Previously, we reported that 5 daily TAM treatments in C3iKO mice at 4‐5 mo of age led to sustained C3 reductions of ∼95% in serum and ∼80% in brain, and protected mice against age‐related cognitive decline at 16‐17 months. In addition, TAM treatment at 3‐4 mo of age protected long‐term potentiation (LTP) in hippocampal slices exposed to toxic Aβ dimers (S26C) obtained at 7‐8 mo of age. Here, we extend our analyses to include changes in complement, cytokine and ApoE expression in these same C3iKO mice and provide confirmatory results in a second cohort of mice.MethodqRT‐PCR was used to quantify brain gene expression in the first cohort. In the second cohort, C3iKO, C3fl/fl and C3KO mice were treated with TAM or corn oil (CO) at 7‐8 mo of age. Cognitive testing commenced at 17‐18 mo and included the Spatial Novelty Y Maze (SPNY), Novel Object Recognition (NOR) and Displaced Object Recognition (DOR). Mice were euthanized and hippocampal synaptosomes isolated for Western blot analysis.ResultOne‐year post‐treatment, C1qa, C1qb, C1qc, C3, CD11b, CD18, IL‐1β, IFNα, IFNβ, and APOE mRNAs were reduced, and TGFβ and TGFβR1 mRNAs were elevated in brains of TAM‐treated C3iKO and C3KO mice compared to CO‐treated C3iKO mice. In the second cohort, C3 protein levels were reduced ∼92% in serum and ∼77% in hippocampal synaptosomes in TAM‐treated C3iKO mice. TAM‐treated C3iKO mice and both C3KO groups showed significantly better performance in SNYM, LOR and DOR tests compared to controls, consistent with our first study. Pre‐ and post‐synaptic markers were elevated in TAM‐treated vs. CO‐treated C3iKO hippocampal synaptosomes.ConclusionGlobal C3 lowering in adulthood has long‐lasting effects on immune signaling and hippocampal function. (NIH RF1 AG060057‐CAL)
Development of Assistive Technology for Instrumental Activities of Daily Living for Dementia Homecare Environments
Authors: Roberts Emily , Fan Guoliang , Chen Xiaowei 
Published: December 2022

AbstractThis presentation describes preliminary National Institute of Health (NIH) funded user‐centered research into Cognitive Assistive Technology (CAT) for dementia homecare and the subsequent development of a lab for testing the CAT. Caregivers face on‐going significant risk throughout the ebb and flow of providing care, as individuals with dementia may lose grasp of their understanding of their circumstances, relying heavily on caregivers for all aspects of their physical and emotional support, as well as prompting and cueing through the multi‐step IADLs. Difficulty with IADL tasks such as cooking meals and housekeeping is one feature of early‐stage dementia, as these tasks require complex cognitive processing and are cognitively demanding. The goal of this research is to improve caregiver resilience and sustainability of dementia homecare via a low‐cost wearable CAT system which can support the IADL task cueing intervention for care recipients called IADL/CAT. IADLs are highly personalized set of needs, requiring a flexible and versatile approach that can be customized and adapted for each individual in a specific setting. Smart‐home technologies and assistive technology tools of specific functionalities have been previously developed to partially address those challenges, however, there is currently a lack of low‐cost, portable, versatile and programmable interventions that can relieve the physical and emotional burden from caregivers by automatically providing timely, needed and individualized IADL task cueing to care recipients Our working hypothesis is that environmental cueing for an individual with dementia can be recorded and replayed to enable timely feedback and assistance through a IADL/CAT wearable device. This presentation will describe the initial research conducted to not only develop an environmental testing lab for the IADL/CAT project, but the initial system navigation cueing through the 3D model retrieval. Through the development of a lab‐based replication/mock‐up of environmental relationships which would be found in a home (i.e. connection between a kitchen and dining room) we have been begun to evaluate the IADL/CAT programming features and system usability.
Building an EEG‐based Alzheimer’s Diagnostic: What is the Optimal Cross‐Validation Method?
Authors: Quirk Colin , Brookshire Geoffrey , Wu Yunan "Charles" , Lucero Ché 
Published: December 2022

AbstractBackgroundAlzheimer's disease lacks a fast, easy, reliable method of diagnosis. Attempts to create classifiers based on brain activity in resting‐state electroencephalography (rsEEG) are promising but require state‐of‐the‐art machine learning models to leverage the available information. Typically, single‐pass cross‐validation (SPCV) is used to select a model, despite work suggesting SPCV introduces bias when many models are considered. Recently, nested cross‐validation (NCV) has been introduced to correct this bias. Here we report which of these two processes yields the most accurate Alzheimer's classifiers in held‐out data.MethodWe simulated data to investigate the problem of detecting Alzheimer's Disease. We drew 225 weakly‐related coefficients from a normal distribution to represent features extracted from rsEEG. To increase the difficulty of the classification problem, highly correlated values were then generated for each of these causally meaningful features. Each iteration, 200 training cases were generated along with 1,000,000 test cases. SPCV and NCV were then employed to choose between over 1000 possible combinations of algorithm, optimization type, and hyperparameter set. Performance was assessed by examining the average AUC of the chosen model on the test data over all iterations of data generation and model selection.ResultComparing generalization performance on holdout data, NCV selected better models than standard SPCV (mean difference = 0.021 AUC, t(64) = 2.19, p < 0.05). SPCV overestimated generalization performance numerically, but non‐significantly (mean difference = ‐0.012 AUC, t(64) = ‐1.11, p > 0.05). In contrast, NCV showed better performance on holdout data compared to training data (mean difference = 0.025 AUC, t(64) = 3.59, p < 0.05). Furthermore, NCV produced significantly different patterns for holdout performance estimates compared to SPCV (mean difference = 0.037 AUC, t(64) = 3.48, p < 0.05).ConclusionAdvanced machine learning models are necessary to take advantage of the large amount of information available in rsEEG activity. These results show that traditional single‐pass cross‐validation may overestimate how well model performance will generalize in the real world. Nested cross‐validation allows us to select models with better diagnostic performance, ultimately leading to better outcomes for patients, even when limited to a small number of training cases.
Assessment of ccf‐Mitochondrial DNA Damage in Cognitive Impairment via NGS: Health Disparities in Mexican Americans
Authors: Reid Danielle M , Barber Robert , Thorpe Roland J. , Sun Jie , Zhou Zhengyang , Phillips Nicole 
Published: December 2022

AbstractBackgroundMexican Americans (MAs) are the fastest growing subpopulation in the US. As this population ages, age‐related diseases such as Alzheimer’s disease (AD) will disproportionately affect MAs. MAs have a unique AD pathogenesis signature when compared to their non‐Hispanic White (NHW) counterparts. MtDNA damage may be implicated in the elevated AD burden among MAs due to the high prevalence of common risk factors for cognitive impairment (CI) including metabolic comorbidities. Mitochondrial dysfunction, oxidative damage to guanosine (8oxoG), and 5kb deletions are well‐documented in AD. MtDNA is particularly vulnerable to damage, which can affect mitochondrial function as well as act as a damage associated molecular pattern when released into the cell‐free space (ccf‐mtDNA), stimulating inflammatory responses. We hypothesize that MAs incur mtDNA damage at an elevated rate due to increased comorbidity burden altering mitochondrial function resulting in increased levels of 8oxoG and the common 5kb deletion.MethodMtDNA from buffy coat and plasma samples of participants enrolled in the Texas Alzheimer’s Research Care and Consortium were amplified using the RepliG mtDNA Amplification kit and were sequenced via NexteraXT on Illumina NextSeq. Somatic oxidative variants and the commonly observed 5kb deletion were quantified in both the buffy coat mtDNA and ccf‐mtDNA. These data were analyzed for association with CI and T2D in both the NHW and MA populations. Further, haplogroup‐associated risk for mtDNA damage and ccf‐mtDNA status was assessed.ResultThus far, we found mtDNA 8oxoG mutations in buffy coat are significantly higher in MAs (females are more affected) compared to NHWs and suggestive evidence indicating CI is related to 8oxoG mutations. Further, we identified specific mtDNA haplotypes conferring increased risk for oxidative damage. Analysis of ccf‐mtDNA indicate an elevated level of oxidative damage.ConclusionOur preliminary findings suggest clinical implications of oxidative mtDNA damage as a risk factor for CI specifically in MA females. These data highlight ethnic/racial differences in oxidative burden potentially elucidating sex‐specific mechanisms contributing to the manifestation of age‐related disease etiology. Such results may ultimately inform precision‐based approaches to design therapeutics for mitigating AD disparities in MAs.
Impact of meningeal and age‐related off‐target binding on longitudinal [18F]MK6240 quantification.
Authors: Tissot Cécile , Lussier Firoza Z , Ferrari‐Souza João Pedro , Servaes Stijn , Bezgin Gleb , Ferreira Pamela C.L. , Bellaver Bruna , Leffa Douglas Teixeira , Therriault Joseph , Vermeiren Marie , Kunach Peter , Stevenson Jenna , Rahmouni Nesrine , Chamoun Mira , Benedet Andréa Lessa , Wang Yi‐Ting , Arias Jaime Fernandez , Kang Min Su , Villemagne Victor L , Tudorascu Dana L , Cohen Ann D , Klunk William E , Baker Suzanne L. , Gauthier Serge , Rosa‐Neto Pedro , Pascoal Tharick A 
Published: December 2022

AbstractBackground[18F]MK6240 tau‐PET can detect changes in the early and late stages of tau tangles accumulation. However, off‐target binding, often observed in the meninges and neuromelanin‐containing cells, can interfere with longitudinal tracer quantification. Here, we investigated the association of longitudinal changes in off‐target and target signals using [18F]MK6240.MethodWe assessed individuals from the TRIAD cohort with [18F]MK6240 tau‐PET and clinical evaluation. Longitudinal analyses included 83 cognitively unimpaired (CU) and 37 cognitively impaired (CI) individuals. Age‐related off‐target binding was estimated comparing 36 CU young individuals (<25 y.o) and 28 CU elderly amyloid/tau negative (40‐65 y.o). A t‐test was used to compare both groups. The ratio between baseline and follow‐up SUVR measured changes in off‐target and target regions. Pearson correlations tested the associations between regions, and Bonferroni analysis corrected for multiple comparisons.ResultAlthough averaged images did not present a striking visual difference in [18F]MK6240 uptake between CU young and elderlies, t‐test revealed significant differences between groups in the cerebellar white matter and subcortical regions (Figure1). Table 1 depicts the percentage of area of selected regions overlapping with the age‐related off‐target binding. Notably, we did not observe a significant association between longitudinal changes in age‐related or meningeal off‐target binding with longitudinal change in target regions (Braak‐II, BraakIII‐IV, BraakV‐VI), whereas changes in target regions were highly correlated (Figure2).ConclusionDespite not being visually perceptible, [18F]MK6240 presents age‐related off‐target binding in subcortical regions, similar to regions reported using [18F]Flortaupicir. The overlap between age‐related off‐target and Braak IV region (∼3%) may lead to the confounding results in quantifying this region. The lack of correlation between off‐target and target [18F]MK6240 changes suggests little influence of the off‐target binding on longitudinal tracer quantification. Our results suggest that although off‐target uptake appears to have a modest influence on longitudinal quantification, it is necessary to consider both age‐related and meningeal off‐target signals for an accurate tracer assessment.
Strong effects of the ABCA1 agonist CS6253 on Amyloidβ42/40 ratio and lipoproteins in cynomolgus monkeys
Authors: Kerman Bilal E. , Noveir Sassan D , Xian Haotian , Meuret Cristiana , Smadi Sabrina , Martinez Ashley E. , Johansson Johannes , Zetterberg Henrik , Parks Bryan A , Kuklenyik Zsuzsanna , Johansson Jan O. , Yassine Hussein N. 
Published: December 2022

AbstractBackgroundATI has discovered a novel molecule, CS6253, for hereditary Apolipoprotein E4 (ApoE4) associated Alzheimer’s disease (AD), which is highly differentiated from other molecules in development by its focus on cholesterol transport. CS6253 is a 26mer peptide optimized for ATP binding cassette transporter A1 (ABCA1) mediated cholesterol efflux, in the brain a rate‐limiting step in cholesterol transport from cells to ApoE. ABCA1 activity, as well as CS6253 in AD mouse models, is associated with improvement in AD pathology.In preparation for human studies, we investigated the effects of the ABCA1 agonist peptide CS6253 on amyloid‐β peptides (Aβ) and lipoproteins in plasma and cerebrospinal fluid (CSF) of cynomolgus monkeys, a species with amyloid and lipoprotein metabolism similar to humans.MethodsCS6253 peptide was injected intravenously to cynomolgus monkeys at various doses in three different studies, 1) a pharmacokinetics (PK) study, 2) a dose‐range finding (DRF) study, and 3) a 30‐day Good Laboratory Practice (GLP) toxicology study. Plasma and CSF samples were collected at several time points before and after treatment. Levels of cholesterol, triglyceride (TG), lipoprotein particles, apolipoproteins, and Aβ were measured using ELISA, ion‐mobility analysis, and asymmetric flow field flow fractionation (AF4). The relationship between the change in levels of these biomarkers was analyzed using multiple linear regression models and linear mixed‐effects models.ResultsCS6253 intravenous injection, within minutes, induced an increase in small, plasma high‐density lipoprotein (HDL) particles. Plasma TG, ApoE, and Aβ42/40 ratio were transiently increased following CS‐6253 intravenous injection, and a non‐significant decrease in CSF APP and Aβ42 was observed. CS‐6253 in plasma displaced ApoE from HDL to intermediate‐density‐ and low density‐lipoprotein (IDL/LDL) sized particles paralleled by transient reductions in total cholesterol and HDL‐cholesterol. In contrast to plasma, CS6253 had no effect on the assessed CSF apolipoproteins or lipids.ConclusionsIn cynomolgus monkeys administration of the ABCA1 agonist CS6253 transiently increased plasma ApoE and TGs which was paralleled by plasma Aβ42/40 ratio increase, providing a strong rationale for following these markers in ensuing human studies.
Characterization of a mouse model as a predictive tool for human Post‐Acute Sequelae of Covid‐19
Authors: Pasinetti Giulio Maria , Trageser Kyle J , Griggs Elizabeth 
Published: December 2022

AbstractBackgroundWhile initial effects of Covid‐19 are concentrated in the respiratory system, numerous neurological symptoms and complications have been documented both during the acute disease course, as well as lingering symptoms following infection. Emerging reports have documented a multitude of transcriptional, proteomic, and homeostatic changes following acute infection. Here, we systematically evaluate a transgenic mouse model, a 5xFAD x hACE2, for its ability to recapitulate key underlying PASC‐pathologies.MethodFive month hACE2 x 5xFAD double transgenic mice were intranasally inoculated with SARS‐CoV‐2 and sacrificed seven days post infection. Murine brain samples from the parietotemporal cortex and hippocampus, and matched postmortem SARS‐CoV‐2 infected, AD, healthy control, and AD + SARS‐CoV‐2 infected brain samples were submitted for RNA‐sequencing. Congruency analyses with upset plots and immunohistochemistry were performed to evaluate the ability of the murine model to recapitulate human findings.Result5xFAD x hACE2 mice exhibited key overlapping transcriptional changes common to humans, including BBB dysfunction, impaired synaptogenesis, and leukocyte dysfunction. Glial activation and distribution of virus was also recapitulated in our mouse model. Through dimensionality reduction and the integration of multimodal data, this model exhibits a similar etiopathogenesis to our findings in human.ConclusionThese studies provide a strong evidentiary basis for the utilization of a 5xFAD x hACE2 mouse model for modelling human PASC. Additional future studies utilizing this model to elucidate mechanisms underlying neuropathogenesis and the investigation of novel therapeutics is warranted.