bluuebunny/crossref_metadata_2025_split huggingface dataset:
Functional network modularity and efficiency supports episodic memory in older adults with amyloid‐beta pathology
Authors: Adams Jenna N. , Chappel‐Farley Miranda G. , Yaros Jessica L. , Taylor Lisa , Harris Alyssa L. , Mikhail Abanoub , McMillan Liv , Keator David B. , Yassa Michael A. 
Published: December 2022

AbstractBackgroundEpisodic memory is one of the first cognitive domains to decline in preclinical Alzheimer’s disease. We investigated whether graph metrics of functional networks, specifically modularity and local efficiency, are related to episodic memory and amyloid‐β (Aβ) positivity in cognitively normal older adults.MethodSixty‐five cognitively normal older adults (mean age 72.3 ± 6.2 years; 62% female) underwent high‐resolution resting state fMRI (1.8mm3, partial acquisition) to measure functional connectivity, 18F‐Florbetapir‐PET to measure Aβ pathology, and cognitive assessment. Resting state fMRI data was processed with CONN. ROIs (n=135) from the Brainnetome Atlas contained within rsfMRI coverage were used to generate ROI‐to‐ROI functional connectivity matrices. Graph measures of modularity (Q) and local efficiency were computed with the Brain Connectivity Toolbox using binary graphs at costs ranging from 5%‐50% of network sparsity (5% step size). Aβ status was determined using a >1.11 SUVR threshold of a composite region spanning the association cortex, resulting in 32% of the sample being classified as Aβ+. Episodic memory was measured using the immediate recall measure of the Rey Auditory Verbal Learning Test (RAVLT A5).ResultAβ+ participants had significantly increased modularity compared to Aβ‐ (Fig1A, p<0.05 for costs 25 and 50), but no differences in local efficiency (Fig1B). There was no significant effect of Aβ positivity on RAVLT A5 performance (t(63)=‐0.67, p = 0.51). However, there were significant interactions between Aβ status and RAVLT A5 with both modularity and local efficiency at most cost functions (Fig2). Better RAVLT A5 performance was associated with higher modularity (Fig2A; ex. cost 25: r = 0.54, p=0.01) and higher local efficiency (Fig2B; ex. cost 25: r = 0.63, p=0.002) within Aβ+ participants, but not Aβ‐ participants (ps>0.36).ConclusionOur findings suggest that increases in functional network modularity and local efficiency within Aβ+ cognitively normal older adults may act as a compensatory mechanism to maintain equivalent levels of episodic memory performance.
Early norming data for engagement and recruitment of diverse populations into ADRD research
Authors: Taikeff Nicole , Pham Tiffany , Bennett Erin E , Caruthers Rebekah , Eddings Fran , Resendez Jason , Jackson Jonathan D. 
Published: December 2022

AbstractBackgroundResearch studies and clinical trials in Alzheimer’s disease and related dementias (ADRD) attract smaller and increasingly less‐representative populations. Enrollment barriers are compounded for historically marginalized and minoritized populations (HMM), despite a higher risk of ADRD. Advancements in participant recruitment, retention, and engagement (RER), and clinical research design are urgently needed to address ADRD disparities and inequities. In light of these critical shortfalls in diverse and representative RER, we aimed to improve the understanding of research awareness and motivations of lay communities.MethodPartnering with a community mobilization firm, we canvassed 15,000 residents of Harris County, TX, a diverse county that broadly generalizes to populations across the United States. Oversampling of multiple HMM communities was conducted to assess enrollment barriers and facilitators, as well as attitudes regarding ADRD and ADRD research. Individuals were contacted via a combination of in‐person and phone canvassing. These detailed canvassing data were paired with geospatial mapping tools to develop robust, dynamic catchment areas.ResultAn initial set of RER norms were developed across HMM and non‐HMM populations; this presentation focuses on stratified norms for Black, Latinx, and East Asian populations intersecting with gender identity and educational attainment to demonstrate the complexity of tailored best practices in RER, as well as identification of HMM subsamples that may be readily engaged in RER for ADRD studies. Using Houston as a case study, these norms were developed in contextualized catchment areas that ascertain the type, prevalence, and intersection of ADRD research barriers. Recommendations to improve diversity and representativeness in ADRD research are additionally summarized for HMM and non‐HMM populations.ConclusionThe current study sought to develop a robust approach to RER centering sustainable and inclusive recruitment into ADRD studies. These data were used to develop detailed RER profiles of general and intersectional HMM populations that may function as initial RER norms, supplanting poorly‐defined catchment area estimates for ADRD study sites. These tools will allow researchers to define communities a priori to limit sampling and recruitment bias, and to determine RER barriers with validity. These data are foundational to advance equitable progress in dementia research.
Trem2R47H NSS; 5xFAD mice display age/disease progression‐dependent changes in plaques and plaque‐associated microglia, and increased plasma neurofilament light chain
Authors: Tran Kristine M , Kawauchi Shimako , Javonillo Dominic I , Da Cunha Celia , Phan Jimmy , Rezaie Narges , Liang Heidi Yahan , Milinkeviciute Giedre , Gomez‐Arboledas Angela , Forner Stefania , Mortazavi Ali , Tenner Andrea J , LaFerla Frank , MacGregor Grant R , Green Kim N 
Published: December 2022

AbstractBackgroundGenome‐Wide Association Studies revealed Triggering receptor expressed on myeloid cells 2 (TREM2) R47H mutation as one of the strongest genetic risk factors for late‐onset Alzheimer’s Disease (AD). In the brain, TREM2 is a transmembrane receptor expressed exclusively by myeloid cells. Many current TREM2*R47H mouse models have observed evidence of cryptic splicing products of the mutant allele, resulting in artefactually reduced protein product. Model Organism Development & Evaluation for Late‐Onset Alzheimer’s Disease (MODEL‐AD) consortium at University of California ‐ Irvine has developed the Trem2
R47H NSS (Normal Splice Site) mouse model where the Trem2 allele is expressed at a level similar to the wild‐type Trem2 allele, with no evidence of cryptic splicing products from the mutant allele.MethodWe generated four groups – WT (C57BL6/J), Trem2
R47H homozygous (HO), 5xFAD, and 5xFAD/ Trem2
R47H HO. Coronal brain slices of 4 and 12‐month‐old mice (n=5/sex/genotype/age) were immunolabeled with Thioflavin‐S for dense‐core plaques, ionized calcium binding adaptor molecule 1 (IBA1) for microglia and lysosome‐associated membrane glycoprotein 1 (LAMP1) for neuritic dystrophy. We also measured plasma neurofilament light chain (NfL) as a surrogate measure of brain damage via Meso Scale Discovery (MSD) technology.ResultSex‐related differences in dense‐core Aß plaque burden and size are found in 4‐month 5xFAD/ Trem2
R47H, where female 5xFAD/ Trem2
R47H mice exhibit increased plaque load compared to 5xFAD mice. In males, stark reductions in plaque load are observed. This sex‐difference is not observed at 12‐month. Examination of IBA1+ microglia at 4‐month reveals significant reductions in microglia volume in both Trem2
R47H and 5xFAD/ Trem2
R47H mice compared to their controls. Notably, there is a significant impairment of plaque‐microglia interaction in 5xFAD/ Trem2
R47H at 4‐month that is rescued at 12‐month. Moreover, we find a significant increase in plaque‐associated neuritic damage in 5xFAD/ Trem2
R47H when immunolabeled with LAMP1 at 4‐month that was also absent at 12‐month. Similarly, plasma NfL levels revealed significant increases in brain damage of 5xFAD/ Trem2
R47H compared to 5xFAD at 4‐month and a trending increase at 12‐month.ConclusionCollectively, these results show the effects of the Trem2
R47H variant on plaque development and downstream pathology, highlighting sex differences as well as age/ disease progression‐dependent changes.
Developing the ‘Good Life’ Model: The Recruitment and Training of ‘Dementia Ambassadors’ to Provide a Novel Coaching Approach for Family Caregivers
Authors: Webster Melinda J , Bouranis Nicole G , Gitlin Laura N. , Gliebus Gediminas Peter 
Published: December 2022

AbstractBackgroundThe Good Life Model is an evidence‐informed service extension program that seeks to improve the quality of daily life for people living with dementia (PLWD) and their caregivers through an integrated, replicable health professional learning service approach. To provide this service, caregivers referred from a neurology clinic are matched to Dementia Ambassadors (DAs), nursing and health profession faculty and graduate students who are trained in family‐centric and nonpharmacological approaches. DAs serve as coaches to telephonically provide disease education, referrals and linkages, support and skills in managing caregiver‐identified care challenges. Good Life offers a service‐learning approach for developing a workforce that is prepared to care for families living with dementia, while improving the quality of daily life for both people living with dementia and their caregivers.MethodsDAs involve various health professionals and students and receive training tailored to their level of expertise in dementia care. Regardless of dementia expertise, key competencies include 1) knowledge about dementia types and etiologies, 2) core clinical signs (e.g., behavioral and psychological symptoms, cognitive and functional decline), 3) knowledge of caregiver experiences, 4) ability to assess care challenges and serve as a coach, and 5) ability to rapidly develop rapport and engage in active listening. Caregivers receive support through bimonthly one hour telephone sessions for up to 12 sessions over 6 months. Biweekly case debriefings provide ongoing oversight and support for DAs.ResultsTo date, 36 caregivers have been referred, with 19 enrolled having completed 123 sessions. Of the 8 caregivers who have completed the 6 month program, all have elected to continue optional post‐program sessions.ConclusionsIn providing access and support to underserved populations with a nonpharmacological phone intervention, Good Life demonstrates not only the need for service extension practices as part of standard dementia care to support PLWD and caregivers, but highlights the importance of preparing a workforce to help caregivers manage challenges. Furthermore, caregivers to date having unanimously elected to continue post‐program sessions attests to the rapid and powerful relationship developed between DAs trained in these practices and the caregivers who gain value from participating.
Validation of Mitochondria‐Targeted AD Therapeutics in Human Neuronal Cells
Authors: Hasan Md Fayad , Nguyen Thi Kim Oanh , Trushina Eugenia 
Published: December 2022

AbstractBackgroundNeurons and astrocytes were differentiated separately from human induced pluripotent stem cells (HiPSC) derived from Late‐Onset Alzheimer Disease (LOAD) female patients carrying Apolipoprotein E4 (ApoE4) allele. Cells from age and sex matched healthy subject carrying Apolipoprotein E3 allele were used as control. These neuronal, astrocytic, and their co‐cultures were assessed to investigate cell‐specific AD phenotypes (Figure 1). We recently demonstrated that application of a small molecule partial mitochondrial complex I inhibitor CP2 blocked neurodegeneration and cognitive decline in multiple mouse models of AD. However, the demonstration that this novel therapeutic approach is efficacious in human brain cells has not been done. Here, we aimed to validate neuroprotective mechanisms induced by CP2 using patient‐derived neuronal cells form LOAD patient. Outcomes will further support the development of these compounds for clinical application.MethodAxonal trafficking of MitoTracker Red stained mitochondria in neuron‐astrocyte co‐cultures was captured using live confocal imaging. The Seahorse XFe96 flux analyzer was used to evaluate mitochondrial bioenergetics in co‐cultures and pure neuronal or astrocytic cultures. Cell Viability Assays were used to perform H2O2 challenge. Quantitative polymerase chain reaction (qPCR), immunohistochemistry, and western blot were carried out to assess alterations in the expression of relevant genes and protein products.ResultWe have found that LOAD cells have a significant reduction in the percentage of motile mitochondria in axons, increased accumulation of neuronal phosphorylated Tau, and altered bioenergetics in neurons and astrocytes compared to the control cells. qPCR revealed elevated expression of inflammation related genes in LOAD co‐cultures. CP2 treatment at concentrations found therapeutically relevant in vivo in APP/PS1 and 3xTgAD mice improved cellular bioenergetics, rescued mitochondrial motility, and provided neuroprotection against H2O2 induced oxidative stress.ConclusionLOAD HiPSC‐derived neuronal co‐cultures and individual brain cells recapitulate mechanisms associated with LOAD allowing validation of a novel mitochondria‐targeted therapeutics. Our results support previous observation in AD mice and the hypothesis that partial inhibition of mitochondrial complex I activates neuroprotective compensatory mechanisms improving cellular energetics in LOAD human neurons even in the presence of mitochondria with abnormal dynamics and energetics. Further efforts are focused on the determination of a cell‐specific mechanisms of neuroprotection.
Using an entorhinal cortex‐based virtual reality navigation task to differentiate between individuals with and without subjective cognitive decline
Authors: Segen Vladislava , Wolbers Thomas 
Published: December 2022

AbstractBackgroundEntorhinal cortex is vulnerable to neurodegenerative changes in the earliest stages of AD. However, this early AD stage cannot be detected by currently available neuropsychological tests. The entorhinal cortex contains spatial modulated cells, known as grid cells, that play a key role in supporting path integration (PI), a crucial component of spatial navigation that supports continuous integration of self‐motion information and in combination with environmental cues provides accurate internal representation of space. Previously, PI deficits were associaed with impaired grid cell function in healthy older adults and in young APOE‐E4 carriers. Importantly, PI performance has successfully discriminated between biomarker positive and negative mild cognitive impairment patients and between healthy older adults at higher and lower risk of AD. In this study, we tested whether performance on an immersive virtual reality PI task can differentiate between patients with and without subjective cognitive decline (SCD).MethodA group of healthy older adults and SCD patients will perform an immersive virtual reality PI task. In this task, participants are immersed in an open‐field virtual environment and are guided along short, curved paths. At certain points they are asked to stop and indicate their initial heading orientation and the location of an object, providing information about distance and orientation coding. During the task participants have access to multisensory self‐motion cues (visual, vestibular and proprioceptive), all of which are pivotal for supporting grid cell function. Additionally, participants will be screened for presence of objective cognitive impairments and will undergo an assessment of their visuospatial working memory and balance.ResultWe will compare if SCD patients perform worse than healthy older controls in the general PI performance measures (e.g., PI error, response time). Furthermore, we will apply a recently developed computational model to identify multiple sources of PI error. This approach allows for a very nuanced characterization of PI deficits, and, as a result, provides additional, potentially even more sensitive markers of very early AD compared to typical PI performance measures.ConclusionThe results will be discussed with reference to the utility of immersive virtual PI as a sensitive biomarker for early, preclinical, AD manifestation.
Cell‐specific responses to Tau pathology in the aging brain
Authors: Wu Timothy , Guo Caiwei , Deger Jennifer Marie , Dhindsa Justin , Al‐Ouran Rami , Shulman Joshua M 
Published: December 2022

AbstractBackgroundGene expression profiling has emerged as a promising unbiased approach to characterize putative mechanisms of Alzheimer’s disease (AD). We previously highlighted transcriptional signatures that are driven by Tau pathology or aging in a longitudinal Drosophila model of tauopathy and human RNA‐sequencing data. However, cellular heterogeneity confounds the interpretation of bulk‐tissue gene expression. Defining cell types and characterizing cell‐specific processes that precipitate neurodegeneration is crucial for elucidating AD pathogenesis.MethodWe use a highly tractable, longitudinal, Drosophila model of tauopathy and single cell transcriptomics (scRNA‐seq) to explore cell‐specific contributions to tau‐mediated gene expression while accounting for age‐related changes. Brains of adult Drosophila pan‐neuronally expressing a mutant variant of human Tau (R406W) and respective controls were dissociated for droplet‐based scRNA‐seq at 1‐, 10‐, and 20‐ days post‐eclosion. We computed differentially expressed genes (DEGs) for each cell subpopulation and profiled gene regulatory networks (regulons), highlighting cell‐specific Tau‐ and aging‐related changes. Tau‐induced changes were compared with previously published bulk RNA‐sequencing data and gene co‐expression networks. To address cross‐species conservation of single cell transcriptional signatures, we leverage published human single nuclei RNA‐sequencing (snRNA‐seq) data.ResultWe identified 96 cell subpopulations clustered by transcriptomic similarities in the adult Drosophila brain and annotated 59 with cell identities. We mapped half of all DEGs identified in our published bulk‐tissue RNA‐sequencing to cell subpopulations. We characterized 183 regulons in our dataset and demonstrated network‐level expression changes driven by Tau. Most Tau‐induced gene expression changes were observed in glutamatergic and cholinergic excitatory neurons while fewer changes were seen in GABAergic inhibitory neurons. Likewise, we observed Tau‐induced reductions in cholinergic and glutamatergic neuron numbers. Correlation of cluster‐specific transcriptional profiles between our data and mammalian snRNA‐seq demonstrate conservation of gene expression among inferred cell identities. Strikingly, we found abundant innate immune gene expression signatures among neuronal subpopulations, and pinpointed cell autonomous Nuclear Factor Kappa B (NFkB) signaling as a modifier in Tau‐induced neurodegeneration.ConclusionOur results comprise a powerful single cell transcriptomic resource for studying tau‐mediated disruption of gene expression and dynamic age‐dependent changes at cellular resolution in a tractable model system.
Cognitive Reserve Moderates the Association Between Cerebral Blood Flow and Language Performance in Older Adults with Mild Cognitive Impairment
Authors: Brenner Einat K , Edwards Lauren , Thomas Kelsey R. , Weigand Alexandra J. , Edmonds Emily C. , Bondi Mark W. , Bangen Katherine J. 
Published: December 2022

AbstractBackgroundIt has consistently been demonstrated that individuals with higher cognitive reserve (CR) exhibit decreased risk for dementia, and differences in cerebral blood flow (CBF) among those with higher CR may offer a protective mechanism against the cognitive changes associated with dementia. We sought to investigate CR as a moderator of the effect of CBF on memory and language performance in patients with mild cognitive impairment (MCI) and those who are cognitively unimpaired (CU).MethodOlder adults from the Alzheimer’s Disease Neuroimaging Initiative (ADNI; N = 46 MCI, 101 CU) underwent neuropsychological evaluation and arterial spin labeling MRI, which was used to quantify CBF in a priori regions. Estimated VIQ from the American National Adult Reading Test was used as a CR proxy. Multiple linear regressions assessed for (1) effect of CR on cognition, (2) effect of CR on CBF, and (3) interaction between CR and CBF on cognition. Cognitive outcomes included memory (word list) and language (category fluency, naming). All models adjusted for age, gender, APOE e4 allele frequency, and education, and interactions additionally adjusted for baseline FDG and pulse pressure.ResultVIQ was not associated with memory but was positively associated with fluency and naming in both groups (ps<0.005). VIQ was not associated with CBF in either group. Individuals with MCI showed a significant interaction between VIQ and CBF on fluency across several regions, including the bilateral hippocampus (p = 0.003), bilateral inferior temporal gyrus (p = 0.008), superior frontal gyrus (p = 0.005), and inferior frontal gyrus (p<0.001). For all models, as CR increased, the magnitude of the association between CBF and performance increased. These interactions were not significant in the CU group. Models with naming or memory as the outcome variable were not significant in either group. Results remained similar when education was not adjusted for.ConclusionThese results suggest that among individuals with MCI, the association between CBF and category fluency is dependent on CR, even after adjusting for several factors. Specifically, higher CR may serve as a protective factor against the negative effect of CBF reductions on fluency. Further research is needed to clarify the role that CR plays as a moderator of CBF and cognition.