bluuebunny/crossref_metadata_2025_split huggingface dataset:
The impact of an innovative intergenerational respite program on workforce development through attitude change in college student volunteers
Authors: Gans Daphna , Guerrero Lourdes , Garcia Maribel , Tan Zaldy S 
Published: December 2020

AbstractIntroductionTimeOut@UCLA is an intergenerational program that trains and mobilizes undergraduate college students to provide companionship to older adults with early stage Alzheimer’s or other forms of dementia. The program goals are: (1) strengthen student interest and experience in geriatrics and gerontology; (2) reduce the isolation of frail older adults; and, (3) support family caregivers. The aim of this study was to determine program’s effect on students' knowledge and attitudes toward people with Alzheimer's disease.MethodsFollowing focused training (in‐person and via online module) on aging and dementia, college students volunteered twice a week for 10 weeks (60 hours) in the TimeOut@UCLA program. Each student was matched with a cognitively‐impaired older adult based on shared interests and fostered intergenerational relationship through conversation and structured activities. The Dementia Attitude Scale (DAS)1, a validated 20‐question, 170‐point scale validated tool and a self‐rated confidence survey in working with seniors were administered before and at the conclusion of the program.ResultsFifty‐three students participated in this study with 41 responded to the survey. The students experienced a significant (P < 0.001) increase (26 points) on the Dementia Attitude Scale following participation in the program. Moreover, 95% (39/41) of the students reported that the intergenerational program improved their ability to work with seniors.ConclusionMeaningful interactions with older adults within the TimeOut@UCLA intergenerational respite program increases college students’ positive attitudes towards, and reported ability to work with, persons with Alzheimer’s or other forms of dementia. With the increasing numbers of persons with dementia, it is imperative to develop programs that reduce the stigma among young people of working with cognitively‐impairment older adults and to promote careers in geriatrics and gerontology.
Depressive symptoms modeled across the life‐course are associated with higher risk of dementia and cognitive decline: A pooled cohort analysis
Authors: Brenowitz Willa D , Hazzouri Adina Zeki Al , Vittinghoff Eric , Matthews Karen A , Golden Sherita H , Fitzpatrick Annette L , Yaffe Kristine 
Published: December 2020

AbstractBackgroundDepression may be an important risk factor for dementia, but findings are controversial, partially because depression may be an early symptom of dementia. Most studies have only assessed depression symptoms at mid or late‐life, although depression can be a lifelong illness and effects may differ over the life‐course, with important prevention implications. We pooled data from 4 prospective cohorts spanning the life‐course to assess associations between life‐course depressive symptoms and risk of mild cognitive impairment (MCI)/dementia and cognitive decline.MethodWe analyzed repeated Center for Epidemiologic Studies Depression Scale‐10 (CESD‐10) assessments for 15,001 adults spanning early adult to mid‐life (CARDIA; N=5,115), mid to late‐life (MESA; N=4,515), and late‐life (CHS; N=5,888 and Health ABC; N=3,075). Using linear mixed models (LMMs), we imputed expected depressive symptom levels from age 20 until the end of follow‐up, then summarized these exposures in early adulthood (ages 20‐49), mid‐life (50‐69), and late‐life (70‐89) by time‐weighted averages (TWAs). Among CHS and Health ABC participants, we used Cox models and LMMs to estimate the associations of higher depressive TWAs from imputed depressive symptoms with incidence of MCI/dementia as well as cognitive trajectories, adjusting for age, sex, race/ethnicity, education, cohort, and anti‐depressant use. In preliminary analyses, depressive symptoms were categorized as low (CESD‐10= 0‐3; reference group), middle (CESD‐10= 4‐10) and high (CESD‐10 >10).ResultIncreased risk of MCI/dementia was associated with elevated depressive TWAs in each life stage: early adulthood HR=1.59 (95% CI: 1.35,1.87); mid‐life HR=1.94 (95%CI: 1.16, 3.26); and late‐life HR=1.77 (95%CI:1.42, 2.21) (Table 1). Higher TWAs in each life‐stage were also associated with faster rates of cognitive decline (all,p<0.05). When adjusted for depressive TWAs in the other life stages, elevated depressive TWAs in early adulthood (HR=1.73; 95%CI: 1.42,2.11) and late‐life (HR=1.43; 95%CI: 1.08,1.89) remained significantly associated with MCI/dementia and faster cognitive decline.ConclusionDepressive symptoms imputed across the life‐course were associated with worse cognition, faster rates of cognitive decline and higher risk of dementia in late‐life. These findings are among the first to suggest that depressive symptoms in early adulthood are associated with higher risk of dementia, independent of the effects of late‐life depression.
The locus coeruleus on stress: Bridging the translational gap
Authors: Bohacek Johannes 
Published: December 2020

AbstractBackgroundLoss of locus coeruleus (LC) neurons is one of the earliest and most pronounced features of Alzheimer's disease (AD). Stress is one of the most powerful activators of LC activity, and a risk factor for the development of AD. However, the small size of the LC, and its location deep in the brainstem, make systematic investigations of this nucleus extremely challenging. Here, we develop translational tools that can link animal and human research to study how stress impacts the LC, and how this might contribute to the risk of developing AD.MethodsFirst, to study how the LC drives functional changes across brain networks, we developed a new chemo‐connectomic approach that combines DREADD/chemogenetic manipulation of the LC with resting‐state fMRI analyses (rs‐fMRI) in mice. Second, we employ pupillometry – a clinically widespread and readily available tool – together with optogenetic LC stimulation to assess the impact of various, physiologically relevant LC stimulation paradigms on pupil diameter. Third, we leverage novel genetic tools to perform multi‐omic molecular screens in the mouse LC, to analyze sex differences and stress‐induced molecular changes.ResultsChemo‐connectomics shows that strong LC activation triggers a rapid network reset and potently activates saliency networks, thus revealing striking similarities between LC activation in the mouse and stress‐related rs‐fMRI data in humans. Pupillometry shows that optogenetic LC stimulation faithfully triggers pupil dilation, a response that scales with stimulation intensity and frequency. Molecular screening reveals – for the first time – the impact of acute stress on the transcriptional and translational landscape of the locus coeruleus, while sex differences appear to be subtle.ConclusionIn combination, these approaches allow us to dissect LC function from molecules to circuits to brain‐wide networks. While pupillometry provides a simple and clinically available window into LC function, chemo‐connectomics holds the potential to identify noradrenaline‐based network signatures that can identify high‐risk populations (or specific subgroups) of AD patients using rs‐fMRI. Finally, the ability to perform high‐throughput molecular screens in mice allows us to explore stress‐induced changes in LC function, and link these changes to neurodegenerative disease processes.
Brain structure and allelic association in Alzheimer’s disease
Authors: Moon Seok Woo , Dinov Ivo D. , Zhao Lu , Matloff William 
Published: December 2020

AbstractBackgroundUsing the Alzheimer’s Disease Neuroimaging Initiative (ADNI) data archive we examined dementia‐related late‐onset cognitive impairment using neuroimaging and genetics biomarkers.MethodWe used FreeSurfer to parcellate the structural brain magnetic resonance imaging (MRI) data to derive homologous imaging signature vectors composed of 1,118 computed imaging biomarkers. The demographics of the 1,026 ADNI 1, ADNI GO and ADNI 2 arms of the ADNI study included participants ages 405 to 85, 266 normal CN’s (CDR = 0, Male:138, Female:128), 572 mild cognitively impaired MCI’s (CDR = 0.5, Male:227, Female:245), and 188 AD patients (CDR = 0.5/1, Male:102, Female:86). We extracted the AD‐related genetic markers and imaging markers for the network analysis. Using Plink, we modelled the genetics data and the using the Pipeline environment we identified single nucleotide polymorphisms (SNPs) associated with the clinical diagnosis. Network analyses were applied to examine multidimensional imaging‐genetics associations.ResultThe expected significant correlations between the SNPs and the neuroimaging phenotypes were confirmed using neuroimaging genetics networking analyses. These results may explain some of the differences among the AD, MCI and NC groups. We identified many associations between neuroimaging markers and genomic markers. For instance, cortical thickness, e.g., left and right hemispheres mean thickness, was more sensitive than regional volume morphometrics in capturing structural brain changes. We also identified salient neuroimaging (NI) markers that played important roles in neuroimaging networks discrimination between CN and MCI groups. However, regional volumes appeared to be more sensitive than thickness measures in discriminating between the MCI and AD groups.ConclusionStructural brain changes are important indicators of dementia progression. Network analysis pairing morphometric biomarkers with genetic indicators allows investigation of clinical and phenotypic associations that facilitate deep systematic understanding of genetic and environmental influences on aging and cognitive decline. Anatomical brain changes reflect the AD complex pathogenesis, their genetic associations, and their longitudinal propagation provide valuable clues to the progression of dementia and differences with normal aging. Further studies are necessary to untangle various deep brain‐networks and interpret their structural association with disease.
The seeding of tau pathology alters the endolysosomal system
Authors: Vazquez‐Sanchez Sonia , Wiersma Vera I. , Kole Jeroen , Jongeneel Rozemarijn , van Beek Roderick , Bebelman Maarten , Scheper Wiep , van Weering Jan 
Published: December 2020

AbstractBackgroundTau pathology and endolysosomal alterations co‐occur in brains of Alzheimer’s Disease and other tauopathy patients, but the relationship between these two pathological features is currently not understood.MethodTau pathology can be modeled in vitro by seeding recombinant tau fibrils on human tau expressing cells, recapitulating tau hyperphosphorylation, misfolding and aggregation. The present study addressed how the seeding of tau pathology impacts the endolysosomal systemin various cell models. Cells expressing human GFP‐tau‐P301L were seeded with pre‐aggregated tau and fixed after 10 days for confocal and 3D‐STED analysis.ResultTau seeds were observed in early and late endosomal/lysosomal compartments. In iPSC‐derived human neurons, the seeding of tau pathology decreased the number, size and EEA1 labelling intensity of EEA1‐positive early endosomes. The effect on early endosomes was specific as the morphology of LAMP1‐positive late endosomes was not affected. Our data however did indicate a decreased proteolytic activity of these compartments suggesting that tau pathology seeding can causally affect endolysosomal function.ConclusionThe seeding of tau pathology can causally induce changes in the endolysosomal system, both on the morphological and the functional level. Such disturbances of this important recycling pathway in neurons may play a critical role in neurodegeneration observed in tauopathies.
Heterogeneous polygenic predisposition to Alzheimer’s disease in the Apolipoprotein E region
Authors: Kulminski Alexander M. , Philipp Ian , Loika Yury , He Liang 
Published: December 2020

AbstractBackgroundDespite recent advances, the role of genetic variants in the ApoE region in Alzheimer’s disease (AD), including ApoE4 and ApoE2 alleles, is still controversial. For example, although most researchers believe that the strongest adverse genetic association between the ApoE4 allele and AD is due to this allele itself, others argue that this link is mediated by variants from non‐ApoE genes in this region. A role of the potentially beneficial ApoE2 allele in AD is even more controversial.MethodWe used the standardized third mixed moment (coskewness) metric, which generalizes linkage disequilibrium (LD) between pairs of single nucleotide polymorphisms (SNPs), to gain insights into a more homogeneous polygenic architecture of AD in the ApoE region. We examined coskewness using genotypes of 32 SNPs representing BCAM‐NECTIN2‐TOMM40‐ApoE‐ApoC1 region in a mega sample of 2,799 AD‐affected and 16,354 unaffected Caucasians from four independent studies. Associations of triples of SNPs with AD were assessed by contrasting the differences in coskewness between AD‐affected and unaffected subjects. We emphasized coskewness for triples harboring ApoE2 (rs7412) and/or ApoE4 (rs429358) coding SNPs.ResultFor 32 SNPs, there were 4,960 triples. The analysis of the mega sample of four studies combined identified 306 triples of SNPs from all five genes associated with AD at Bonferroni‐adjusted significance level (p < 10−5 = 0.05/4960). Of them, 275 triples (90%) were validated by examining consistency of directions of the associations in two subsets of independent studies comprising this mega sample that is widely regarded as replication. Of these 275 validated triples, 43 triples included rs429358 and 17 triples included rs7412. In addition, three triples included both these SNPs and SNPs from TOMM40 (rs2075650), ApoE (rs405509), and ApoC1 (rs12721046) genes. For a vast majority of validated triples, the associations with AD were not explained by pairwise LD between SNPs.ConclusionThese results indicate AD‐associated structuring genetic processes in Caucasians. They provide compelling support for heterogeneous polygenic predisposition to AD in the ApoE region in the form of compound genotypes and haplotypes. They suggest coherent, rather than independent, role of the ApoE2 (rs7412) and ApoE4 (rs429358) coding SNPs and other SNPs in the ApoE region in AD.
World Alzheimer Report 2019: Attitudes to dementia, a global survey
Authors: Lynch Chris 
Published: December 2020

AbstractBackgroundIn 2019 Alzheimer’s Disease International (ADI) undertook the biggest global survey on attitudes to dementia, with 70,000 people across 54 countries participating. Alongside expert essays, case studies and programmes to tackle stigma, the survey results formed the core of the 2019 World Alzheimer ReportMethodADI commissioned London School of Economics & Political Science to create and design a global survey engaging 4 distinct audiences: people living with dementia, carers, healthcare professionals and the general public. The survey was distributed online, through the ADI network, with an offline/supported option for assisted completion.ResultHeadlines. 95% of respondents think they will develop dementia in their lifetimes. 78% are concerned. 2 in 3 people think dementia is a normal part of ageing. 62% of healthcare practitioners that resounded believe dementia is a normal part of ageing. 1 in 4 believes there is nothing you can do about it. 82% would take a genetic test. 54% believe lifestyle factors play a part in developing dementia.ConclusionThree years after the introduction of the WHO Global action plan on dementia, with a clear objective of raising awareness, it is evident that stigma is still one of the major barriers to people seeking out information, advice, support and even a diagnosis. Increasing awareness and tackling stigma is vital, not only to help improve the lives of those living with a diagnosis but to ensure that risk reduction messages have impact. There is evidently also still a need to improve understanding of dementia as a medical condition, and not just a normal part of ageing, for both the general public but also healthcare practitioners.
Proteomics studies to investigate alterations in the tau interactome under conditions of elevated cellular O‐GlcNAcylation
Authors: Choi Jinkuk , Walther Dirk M. , Bajrami Bekim , Halftermeyer Anais , Rajamohamed Sait Hameetha Banu , Okugawa Naomi , Engle Sandra J. , Wei Ru , Hering Heike 
Published: December 2020

AbstractBackgroundNeurofibrillary tangles consist of tau protein aggregates and represent a hallmark pathology of Alzheimer’s disease. Tau aggregation, specifically the formation of early aggregates, is believed to be neurotoxic. O‐linked glycosylation of proteins with β‐linked N‐acetylglucosamine (O‐GlcNAcylation) is exclusively mediated by two enzymes in cells, O‐GlcNAc transferase (OGT) and O‐GlcNAcase (OGA). Importantly, increasing O‐GlcNAcylation attenuates tau aggregation in cell‐free systems and cells and reduces tau pathology in various animal models, but the underlying molecular mechanism is still unclear. We aimed to determine how protein‐protein interactions of tau are affected by altered O‐GlcNAcylation levels in cells.Method(1) Immunoprecipitation of tau complexes and nano LC‐MS/MS analysis (IP‐MS) were performed to detect changes in tau binding proteins in HEK293T cells, upon elevated O‐GlcNAcylation by OGT overexpression and OGA inhibition. (2) Proximity labeling by TurboID, an engineered biotin ligase, fused to either wild‐type or O‐GlcNAcylation‐resistant mutant tau and nano LC‐MS/MS analysis were performed to assess changes in the proximity of tau to other proteins in iPSC‐derived human cortical neurons (iN), after increasing O‐GlcNAcylation by OGA inhibition.Result(1) We detected proteins that constitutively or differentially interact with tau from IP‐MS experiments in HEK293T cells. Microtubule and cytoskeletal proteins were consistently bound to tau regardless of changes in cellular O‐GlcNAcylation. RNA binding proteins and ribosomal proteins increased but cytosolic/exosome proteins and chaperone proteins decreased their interaction with tau upon elevated cellular O‐GlcNAcylation. (2) Proximity labeling of proteins by TurboID‐tau in iN successfully identified microtubule‐associated proteins and proteins that were previously reported to interact with tau in the brain. Interestingly, six proteins significantly changed their proximity to O‐GlcNAcylation‐resistant mutant tau, whereas increased O‐GlcNAcylation by OGA inhibition did not change the proximity labeling profile of wild‐type or mutant tau proteins.ConclusionThese results demonstrate that increasing cellular O‐GlcNAcylation does not significantly alter the general subcellular localization of tau, but affects its interaction with specific binding partners, some of which were previously implicated to play important a role in neurodegeneration. These data may provide novel mechanistic insights into how O‐GlcNAcylation impacts tau pathology.
Long‐term synaptic depression and memory deficits are reversed by enhancement of GirK‐dependent signaling in a mouse model of early amyloidopathy
Authors: Jimenez‐Diaz Lydia , Sanchez‐Rodriguez Irene , Djebari Souhail , Temprano‐Carazo Sara , Yajeya Javier , Iborra‐Lázaro Guillermo , Vega David , Jimenez Raquel , Navarro‐Lopez Juan D. 
Published: December 2020

AbstractBackgroundHippocampal synaptic plasticity disruption by amyloid‐β (Aβ) peptides is thought to be responsible for learning and memory impairments in Alzheimer's disease (AD) early stage. Failures in neuronal excitability maintenance seems to be an underlying mechanism. G‐protein‐gated inwardly‐rectifying potassium (GirK) channels control neural excitability by hyperpolarization in response to many G‐protein‐coupled receptors activation.MethodHere, in early in vitro and in vivo amyloidosis mouse models, we study whether GirK channels take part of the hippocampal synaptic plasticity impairments generated by Aβ
1‐42. In vitro electrophysiological recordings from slices showed that Aβ
1‐42 alters synaptic plasticity by switching high frequency stimulation (HFS) induced long‐term potentiation (LTP) to long‐term depression (LTD), which led to in vivo hippocampal‐dependent memory deficits.ResultRemarkably, selective pharmacological activation of GirK channels with ML297 rescued both HFS‐induced LTP and habituation memory from Aβ
1‐42 action. Moreover, when GirK channels were specifically blocked by Tertiapin‐Q, their activation with ML297 failed to rescue LTP from the HFS‐dependent LTD induced by Aβ
1‐42. On the other hand, the molecular analysis of the recorded slices by western blot showed that expression of GIRK1/2 subunits, which form the prototypical GirK channel in the hippocampus, was not significantly regulated by Aβ
1‐42. However, immunohistochemical examination of our in vivo amyloidosis model showed Aβ
1‐42 to downregulate hippocampal GIRK1 subunit expression.ConclusionTogether, our results describe an Aβ‐mediated deleterious synaptic mechanism that modifies the induction threshold for hippocampal LTP/LTD and underlies memory alterations observed in amyloidosis models. In this scenario, GirK activation assures memory formation by preventing the transformation of HFS‐induced LTP into LTD.
Morphofunctional changes and expression of LAMP2 in the rat hippocampus in chronic cerebral ischemia
Authors: Smirnov Alexey Vladimirovich , Mednikov Dmitry , Tyurenkov Ivan Nikolaevich , Kurkin Denis , Zamlelov Alexander 
Published: December 2020

AbstractBackgroundThe hippocampus, part of the limbic system, is involved in the formation of the cognitive sphere and is one of the most vulnerable structures in chronic cerebral ischemia.MethodChronic cerebrovascular disorders modeled in rats by limiting blood flow with applying ligatures to the carotid arteries. Behavioral status, cognitive and mnemonic functions, the degree of neuronal damage, and the level of LAMP2 expression in the pyramidal layer of the hippocampus were investigated.ResultAfter a 20‐day subtotal cerebral ischemia, we revealed a change in the functional state of the nervous system, expressed in a decrease of the main reflexes, tentative‐research activity, as well as a decrease in memory. Dystrophic changes in pyramidal neurons were of different severity, determined by a significant increase in the number of hyperchromic neurons, and in most of them total nuclear and cytoplasmic hyperchromia was observed, combined with a picture of spongiosis due to pericellular edema. A significant increase in LAMP2 expression compared to the control in both the relative area by 0.8% (p <0.05) and the intensity of the expression was detected in the CA1 zone.ConclusionThe amplification of LAMP‐2 expression is a marker for the inclusion of autophagy mechanisms aimed at implementing compensatory processes in many disorders of the central nervous system, including chronic cerebral ischemia. The observed increase in the specific number of pyramidal neurons with signs of damage, sharp pericellular and perivascular edema in combination with increased expression of LAMP‐2 in the CA1 zone of the hippocampus indicates the important role of autophagy for the survival of neurons in chronic cerebral ischemia.