bluuebunny/crossref_metadata_2025_split huggingface dataset:
Uncovering the Quantitative Relationships Among Chromosome Fluctuations, Epigenetics, and Gene Expressions of Transdifferentiation on Waddington Landscape
Authors: Chu Wen‐Ting , Chu Xiakun , Wang Jin 
Published: February 2022

AbstractThe 3D spatial organization of the chromosomes appears to be linked to the gene function, which is cell type‐specific. The chromosome structural ensemble switching model (CSESM) is developed by employing a heteropolymer model on different cell types and the important quantitative relationships among the chromosome ensemble, the epigenetic marks, and the gene expressions are uncovered, that both chromosome fluctuation and epigenetic marks have strong linear correlations with the gene expressions. The results support that the two compartments have different behaviors, corresponding to the relatively sparse and fluctuating phase (compartment A) and the relatively dense and stable phase (compartment B). Importantly, through the investigation of the transdifferentiation processes between the peripheral blood mononuclear cell (PBMC) and the bipolar neuron (BN), a quantitative description for the transdifferentiation is provided, which can be linked to the Waddington landscape. In addition, compared to the direct transdifferentiation between PBMC and BN, the transdifferentiation via the intermediate state neural progenitor cell (NPC) follows a different path (an “uphill” followed by a “downhill”). These theoretical studies bridge the gap among the chromosome fluctuations/ensembles, the epigenetics, and gene expressions in determining the cell fate.
Quantifying Cell‐Derived Changes in Collagen Synthesis, Alignment, and Mechanics in a 3D Connective Tissue Model
Authors: Wilks Benjamin T. , Evans Elisabeth B. , Howes Andrew , Hopkins Caitlin M. , Nakhla Morcos N. , Williams Geoffrey , Morgan Jeffrey R. 
Published: February 2022

AbstractDysregulation of extracellular matrix (ECM) synthesis, organization, and mechanics are hallmark features of diseases like fibrosis and cancer. However, most in vitro models fail to recapitulate the three‐dimensional (3D) multi‐scale hierarchical architecture of collagen‐rich tissues and as a result, are unable to mirror native or disease phenotypes. Herein, using primary human fibroblasts seeded into custom fabricated 3D non‐adhesive agarose molds, a novel strategy is proposed to direct the morphogenesis of engineered 3D ring‐shaped tissue constructs with tensile and histological properties that recapitulate key features of fibrous connective tissue. To characterize the shift from monodispersed cells to a highly‐aligned, collagen‐rich matrix, a multi‐modal approach integrating histology, multiphoton second‐harmonic generation, and electron microscopy is employed. Structural changes in collagen synthesis and alignment are then mapped to functional differences in tissue mechanics and total collagen content. Due to the absence of an exogenously added scaffolding material, this model enables the direct quantification of cell‐derived changes in 3D matrix synthesis, alignment, and mechanics in response to the addition or removal of relevant biomolecular perturbations. To illustrate this, the effects of nutrient composition, fetal bovine serum, rho‐kinase inhibitor, and pro‐ and anti‐fibrotic compounds on ECM synthesis, 3D collagen architecture, and mechanophenotype are quantified.
Supporting people living with dementia and care partners throughout the COVID‐19 pandemic: Health service directions from the first wave in Calgary, Alberta
Authors: Roach Pamela , Zwiers Angela , Cox Emily , Fischer Karyn , Charlton Anna , Josephson Colin B , Patten Scott B , Seitz Dallas , Ismail Zahinoor , Smith Eric E. ,   The PROMPT Collaborators
Published: February 2022

AbstractBackgroundThe emergence of COVID‐19 (SARS‐CoV‐2) as a novel coronavirus in late 2019 necessitated public health measures that have impacted the provision of care for people living with dementia and their families. The rapid shift to virtual care across health and social care sectors meant that providers did not have the opportunity to benefit from an evidence‐based understanding about how and which services can safely and effectively be delivered virtually prior to public health measures being implemented. Additionally, isolation resulting from social distancing may be harming well‐being for families as formal and informal supports become less accessible.MethodTo understand lived experiences and necessary changes in models of care delivery for people living with dementia during the COVID‐19 pandemic in Canada, we remotely interviewed 20 dyads of people living with dementia and their care partners who normally attend a dementia specialty clinic in Calgary, Alberta, during a period where essential businesses were closed and health care had abruptly transitioned to telemedicine. Participants were 50% female and a majority of clinic patients in the dyad had a diagnosis of Alzheimer’s Disease (75%). A reflexive thematic analysis was used to analyze the interview and field note data.ResultThemes regarding virtual service provision emerged through the iterative qualitative data analysis: (1) continuation of community‐based services for care partners and families delivered in innovative ways to meet support needs during the pandemic; (2) guidance in adapting to technology to enable accessible and effective treatment in a virtual care environment; (3) adapting the process and structure of virtual appointments to operationalize critical information provision while maintaining dignity for the person living with dementia.ConclusionThe rapid move to virtual healthcare has influenced how and when people access health services. Health system innovation in the way we structure service models and care provision can mitigate barriers to maintaining high quality virtual health care for people living with dementia. In‐depth understandings of how health systems can provide high‐quality care in new virtual settings is key to maintaining quality of life for community‐dwelling people living with dementia and care partners in times of public health emergencies.
A graph theory approach to detect age and Alzheimer’s disease related changes to structural neural networks
Authors: Wright Laura , De Marco Matteo , Venneri Annalena 
Published: February 2022

AbstractBackgroundChanges to the structural and functional integrity of brain systems are a prominent feature of both Alzheimer’s disease (AD) and the normal ageing process. Recently, research in human brain connectomics has seen many studies adopting graph theoretical methods to explore brain network topology. However, conflicting evidence surrounding disease‐related alterations in structural covariance networks, leaves a gap in our understanding of how system level structural changes may distinguish healthy ageing from disease. The present study, therefore, aimed to establish differences in structural network topology between the stages of healthy ageing and in differing types and severities of cognitive decline.MethodStructural MRI scans were collected for three groups of healthy adults, spanning the age ranges 21‐39 (n = 40), 40‐64 (n = 40) and 65 and over (n = 40), and 3 patient groups including adults with amnestic mild cognitive impairment (aMCI, n = 40), non‐amnestic MCI (n = 30) and Alzheimer’s dementia (n = 40). Structural brain networks were quantified using the volumes of 246 regions of interest, defined by the Brainnetome Atlas (Fan et al., 2016). Graphs were then created for each group with nodes corresponding to brain regions and edges quantified according to the strength of inter‐regional partial correlations.ResultDifferences in global network parameters between healthy groups were limited. Furthermore, non‐amnestic patients showed no differences in average network parameters compared with any healthy group. aMCI and dementia patients demonstrated significantly higher global efficiencies than the youngest and oldest healthy groups. aMCI patients also presented with significantly lower clustering coefficients than all other groups. Network hubs differed substantially between groups. Centrality in frontal lobes was significantly higher in older healthy adults than aMCI patients, dementia patients and both younger groups. Hubs in dementia patients instead shifted to Alzheimer‐related parietal and temporal regions.ConclusionDespite uncertainties surrounding the biological underpinnings of volumetric covariance within the brain, the results presented here, in agreement with previous studies, have demonstrated a utility of structural covariance networks in identifying AD specific changes in the structure of cortical networks. A non‐linear progression of network alterations suggest that such changes may be best appreciated at prodromal disease stages.
Development of a digital system to assess and manage care and support needs of family dementia caregivers
Authors: Klein Olga A ,   DZNE GAIN Research Group
Published: February 2022

AbstractBackgroundA dementia diagnosis has an effect on an entire family who often takes on carer responsibilities for the person diagnosed. Due to this impact, taking on a dyadic perspective to identify care and support needs of caregivers to promote wellbeing and minimise caregiver related burden is necessary. Digitally supported interventions have the potential to be time‐efficient and ensure prompt service provision. Therefore, our aim was to develop a digital system to identify and manage care and support needs of family dementia caregivers.MethodThe development of the system was part of a randomised controlled trial examining the effectiveness of a computer‐based care management programme for family caregivers. Evidence‐based Dementia Care Management as conducted and adapted in several primary care studies in Germany was used as conceptual framework. Using a participatory approach with 27 caregivers and experts including neurologists, psychologists and psychiatrists, we developed a digital system including a self‐completion unmet needs assessment focusing on caregivers’ health und quality of life in connection to their caregiver responsibilities. The system was piloted for its content and technical usability in a memory clinic.ResultThe unmet needs assessment comprises several validated questionnaires with 57 questions examining a person’s self‐reported unmet needs (Camberwell Assessment of Need for the Elderly, CANE), health‐related quality of life (EQ‐5D‐5L), caregiver burden (Zarit Burden Interview, ZBI), social support (Lubben Social Network Scale, LSNS), the use of medical and non‐medical services and resource utilisation. In total, the assessment covers 51 health and support related aspects. The system is able to instantly generate results identifying a person’s unmet needs through predefined algorithms. For each case, the system generates a systematic, written feedback for the participant’s treating GP and it provides a monitoring option capturing the progress of reducing a person’s unmet needs. The assessment, outcome data and system will be presented in detail.ConclusionThe digital system may improve healthcare and support provision for family caregivers of people with dementia by addressing their unmet needs in connection to their caregiver responsibilities. It is necessary to address multiple dimensions of health and provide dyadic assessment and care for better outcomes.
Age‐related atrophy persists after screening for preclinical Alzheimer disease
Authors: Koenig Lauren N. , LaMontagne Pamela J. , Glasser Matthew F. , Gordon Brian A. , Morris John C. , Shimony Joshua S. , Benzinger Tammie L.S. 
Published: February 2022

AbstractBackgroundBrain atrophy has been shown to occur with age, but it is unclear if this is misattribution of undetected preclinical Alzheimer disease (AD). Here we determine regional patterns of age‐related atrophy in a cross‐sectional cohort screened for the confounding influence of preclinical Alzheimer disease.MethodWe assembled two dementia‐free cohorts ‐ a Normal Aging Cohort (n=383) and a Preclinical AD Cohort (n=115) ‐ using participants from The Open Access Series of Imaging Studies and non‐mutation carriers from the Dominantly Inherited Alzheimer Network. The Preclinical AD Cohort was positive by amyloid PET scan. The Normal Aging Cohort was amyloid negative and remained cognitively normal longitudinally. Linear models assessed age‐related atrophy for volumes and cortical thicknesses directly and by using the estimated derivative of smoothed aging curves to assess non‐linear patterns. Amyloid positivity by regional volume/thickness was modeled using multiple linear regressions on the subset of the Normal Aging Cohort above age 60 and the Preclinical Alzheimer Disease Cohort.ResultThe greatest age‐related atrophy was seen in the temporal lobe and subcortical regions, but nearly all regions showed some level of atrophy (Figure 1A). The age‐derivative pattern (Figure 1B) indicated that the temporal lobe linearly declined with age, subcortical regions declined faster at later ages, and frontal regions declined to a lower extend in late life than at midlife. This pattern was significantly associated with an average T1/T2 myelin map from a separate cohort, while the linear measure of age‐related atrophy was not. Volumes and cortical thicknesses in our Preclinical Alzheimer Disease Cohort were not detectably different than our Normal Aging Cohort, with no regions showing significance for amyloid status or age*amyloid status after multiple comparisons correction.ConclusionRegional variability exists both in the amount of atrophy that occurs with age and in the pattern of decline observed, the second of which may be related to myelination. Regional measures of age‐related atrophy do not appear to require screening from preclinical Alzheimer disease.
Cultural construction of ADRD among Alaska natives and providers in Alaska
Authors: Lewis Jordan P 
Published: February 2022

AbstractBackgroundThe proportion of the Native population aged 65+ is projected to increase between 2015 and 2045, from 7‐12%, and health care providers are ill‐prepared to meet the demand of Alzheimer’s Disease and related disorders (ADRD). There is an increasing urgency to better understand Alaska Native views of ADRD.MethodGuided by Kleinman’s explanatory model of illness, a qualitative, research design was utilized to gather data on experiences with ADRD. 21 interviews with Alaska Native caregivers and 12 interviews with health care providers in rural and urban communities were completed. Using Nvivo qualitative software, thematic analysis was used to obtain cultural perspectives on ADRD. This study was approved by the University ad tribal review boards.ResultMany Alaska Natives view ADRD as a natural part of the aging process, resulting in not always seeking medical care. Caregivers challenges included family denial, exhaustion and isolation, and family distancing themselves due to fear and limited understanding of ADRD. Caregiving benefits included spending time with older adult, learning family history, and sharing experiences with other caregivers. Healthcare provider challenges included rigidity of the healthcare system, no research on Alaska Natives, limited health literacy, limited community resources, and no knowledge of Alaska Native views of ADRD.ConclusionUnderstanding the cultural underpinnings of ADRD provides insight into how health care providers can integrate cultural beliefs into treatment to improve the processes of care that may mitigate the impact of ADRD on individuals and families. Culturally‐responsive education and training about ADRD is crucial to connecting Alaska Natives with ADRD to care that can assist them in aging more comfortably.
Disentangling Alzheimer’s disease neurodegeneration from typical brain aging using MRI and machine learning
Authors: Hwang Gyujoon , Abdulkadir Ahmed , Erus Guray , Habes Mohamad , Pomponio Raymond , Shou Haochang , Doshi Jimit , Mamourian Elizabeth , Rashid Tanweer , Bilgel Murat , Fan Yong , Sotiras Aristeidis , Srinivasan Dhivya , Morris John C. , Marcus Daniel S. , Albert Marilyn S. , Bryan Nick , Resnick Susan M. , Nasrallah Ilya M. , Davatzikos Christos , Wolk David A. 
Published: February 2022

AbstractBackgroundNeuroimaging biomarkers that discriminate between healthy brain aging (BA) and Alzheimer’s disease (AD) are valuable in assessing the heterogeneity of neurodegeneration. Prior work has demonstrated that machine learning can detect patterns of brain change related to the two processes on an individual level (including the SPARE [Spatial Patterns of Atrophy for REcognition]‐AD and SPARE‐BA indices investigated herein). However, the substantial overlap between brain regions affected in AD and BA confounds our ability to measure them independently. We present a methodology, and associated results, toward disentangling the two.MethodT1‐weighted MR images of 4,078 participants (48‐95 years) with AD, mild cognitive impairment (MCI), or cognitively normal (CN) diagnoses from the iSTAGING (Imaging‐based coordinate SysTem for AGIng and NeurodeGenerative diseases) consortium were analyzed. First, a subset of 711 patients with probable AD and 711 age‐ and sex‐matched probable CN adults were selected based purely on clinical diagnosis to train multivariate models of brain age (SPARE‐BA1; regression of age using CN) and of an AD index (SPARE‐AD1; classification of CN versus AD). Second, analogous groups a+AD and a‐CN were selected based on clinical and molecular markers (a+AD: 711 amyloid‐positive subjects with AD/MCI, as well as amyloid‐ and tau‐positive CN adults; a‐CN: 711 amyloid‐negative CN adults). Finally, the combined group of a‐CN and a+AD was used to train SPARE‐BA3 model, with the notion that it would avoid AD‐related changes.ResultSeveral subcortical brain regions became more weighted in the SPARE‐BA3 model than in SPARE‐BA1 and SPARE‐BA2, while regions in the temporal and occipital lobes became more weighted in SPARE‐AD2. The correlation between the brain age gap (SPARE‐BA minus chronological age) and SPARE‐AD in the a‐CN group was reduced to insignificant levels (r=0.29 to ‐0.06). While both SPARE‐AD scores well separated AD from CN (area‐under‐the‐curve [AUC]>0.89), the brain age gap with SPARE‐BA3 (AUC=0.63) performed worse compared to SPARE‐BA1 (AUC=0.82). SPARE‐BA3 was generally less correlated with cognition and amyloid biomarkers in patients with AD than SPARE‐BA1, while SPARE‐AD2 demonstrated similar correlations compared to SPARE‐AD1.ConclusionBy employing conservative molecular diagnoses and decoupling SPARE‐BA from SPARE‐AD, we achieved more dissociable neuroanatomical biomarkers of healthy brain aging and AD.
Initial biological evaluation of a novel microtubule‐based PET ligand in rodent and NHP models of AD
Authors: Damuka Naresh , Macauley Shannon L. , Orr Miranda E. , Shively Carol A. , Lockhart Samuel N. , Bansode Avinash , Frye Brett M. , Mintz Akiva , Kim Jeongchul , Register Thomas C. , Whitlow Christopher T. , Craft Suzanne , Solingapuram Sai Kiran K. 
Published: February 2022

AbstractBackgroundMicrotubule (MT) integrity is critical for cell function and viability. Abnormal MT stability is commonly attributed to hyperphosphorylation of the MT‐associated protein, tau. However, the time course of MT instability in disease progression remains unknown. In vivo MT imaging offers an opportunity to gain critical information on MT changes in relation to staging of ADRDs. Our lab reported the first brain‐penetrant MT PET ligand, [11C]MPC‐6827 and evaluated in vivo imaging in normal rodents and non‐human primates (NHP). Herein we report its initial biological evaluations in (a) cells, (b) tau knock‐out mice, and (c) aged NHPs (Caribbean‐origin vervets) with changes in AD‐related biomarkers.MethodIn vitro [11C]MPC‐6827 cell uptake assay was performed in patient‐derived SH‐SY5Y cells with different MT destabilizing and stabilizing agents. Radioactive binding was determined as %ID(injected dose)/mg of protein present in each well. Dynamic 0‐60 min brain microPET/CT imaging was performed in tau knock‐out and wild‐type mice (n=4). Four vervets (20‐29y) with different cerebrospinal fluid (CSF) Aβ42 levels (2 high levels‐1461, 1614 and 2 low levels‐579,732) underwent 0‐120 min brain PET/CT imaging with [11C]MPC‐6827. ROIs were drawn on the whole‐brain and SUVR values were calculated from co‐registered PET/MR images.ResultIn vitro cell uptake assays with [11C]MPC‐6827 in SH‐SY5Y cells displayed high uptake with MT destabilizing agents and low uptake with stabilizing agents. MicroPET imaging demonstrated higher radioactive brain uptake in tau knockout over wild‐type mice. Vervets with low CSF Aβ42 levels showed high radioactive brain uptake and the youngest vervet (20y) displayed lowest brain uptake.ConclusionConsistent with our in vitro cell uptake and in vivo rodent imaging experiments, [11C]MPC‐6827 increased with MT destabilizations. Radioactive uptake was inversely related to CSF Aβ levels and directly related to age in a NHP model of AD (Fig 1). Collectively our data suggest that [11C]MPC‐6827 is more selective towards destabilized MTs. On‐going experiments include rigorous PET imaging analyses, determination of metabolic plasma‐blood parameters, and correlations with Aβ42 and tau levels. Nonetheless, our promising results support the high translational utility of [11C]MPC‐6827 to image MTs in ADRDs.
Lateralized tau deposition and speech, language, and cognition: A descriptive case report
Authors: Longhini Kelly , Betthauser Tobey J. , Koscik Rebecca L. , Williams Victoria J. , Jonaitis Erin M. , Van Hulle Carol A. , Chin Nathaniel A. , Hermann Bruce P. , Christian Bradley T. , Johnson Sterling C. , Mueller Kimberly D. 
Published: February 2022

AbstractBackgroundAsymmetric binding patterns in tau PET imaging are sometimes observed, but less is known about how this asymmetry might explain clinical phenotypes and AD variants, especially in a longitudinal context. Previous work has demonstrated that unilateral tau deposition in left frontal and temporal regions is common in logopenic progressive aphasia (lvPPA), an atypical AD variant. This work presents two descriptive case studies of participants with opposing laterality of [18F]MK‐6240, a PET radioligand for AD neurofibrillary tangles.MethodTwo participants from the Wisconsin Registry for Alzheimer’s Prevention (WRAP), an ongoing, longitudinal cohort study of late middle‐aged adults enriched for AD risk, were identified based on unilateral MK‐6240 deposition. Topographic amyloid and tau burden was assessed with [11C]PiB and [18F]MK‐6240 PET imaging, respectively. Demographic data, cognitive diagnoses, health histories, and APOE status are described. Longitudinal neuropsychological assessments and digitally recorded connected speech samples were analyzed to create a descriptive profile of cognition and connected speech‐language (CSL). Cognitive test scores and language measures were then compared against the scores of the full WRAP sample, using a robust normative approach previously described by our group.ResultMK‐6240 tau‐PET imaging revealed right‐lateralized tau in Participant A and left‐lateralized tau in Participant B (Figure 1). Participants were identical on all demographics except age and APOE risk of developing AD (though both participants were ApoE‐4 allele carriers) (Table 1). Cognitive assessment Z‐scores (0=mean of demographically similar cognitively stable WRAP participants; Figs 2‐4) depict considerable between visit variability for Participant A on all measures, including language and CSL, with decline from baseline on all but letter fluency. Participant B showed isolated baseline deficits on memory tests (AVLT and story recall) at two standard deviations below the mean, which declined further across visits, whereas performances on Trails, naming, category fluency, and all measures of CSL remained stable and within normal expectations.ConclusionIn this case study, right>left tau PET signal was associated with greater decline in language, particularly connected speech and naming. Future work will examine associations between volumetric MRI and asymmetric regional tau deposition, as well as additional relationships to language and cognition.