bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comparing multiple clustering approaches to understand proteomic datasets for improved biomarker detection
Authors: Winchester Laura , Shi Liu , Kormilitzin Andrey , Nevado‐Holgado Alejo J 
Published: December 2020

AbstractBackgroundDevelopment of reproducible blood‐based protein biomarker for Alzheimer’s Disease would allow clinicians and researchers to diagnose and potentially treat patients in the early stages of disease. However, differences found between measurement approaches prevent global marker development. By testing clustering and classification approaches we hope to find commonly co‐expressed markers in the data that can used cross platform and patient cohort to predict disease.MethodSix proteomics datasets with a sample size greater than 100 containing AD cases and controls were collated. We included datasets generated by either mass spectrometry or SomaScan assay from serum, CSF and brain tissue. Each sample set was normalised and analysed through an identical pipeline of unsupervised clustering and network module approaches. These approaches included partitioning, biclustering, density based and fuzzy clustering methods. Bioinformatics tools for module generation tools were also tested (including WGCNA). Methods were compared by cluster/module number and accuracy. Protein lists generated were compared to assess precision.ResultVariability in clustering approach results as well as datasets illustrated the vital importance in quality control and proper normalisation of data. Dimensional reduction was a favoured approach for identification of relevant clustering. In particular Uniform Manifold Approximation and Projection (UMAP) demonstrated its robustness as a tool against the proteomics noise. As well as direct overlap a measure of accuracy was calculated to understand the reliability of the method. We found noisy data was represented by an increased number of predicted clusters with certain algorithms being particularly susceptible such as Principle Component Analysis (PCA) and hierarchical clustering.ConclusionProteomic data has higher background noise and therefore standard genomic approaches designed for gene expression data are not always suitable. We provide recommendations for informatics tools for successful analysis of proteomic data and demonstrate potential testing methods for use on other datasets.
The importance of personal possessions in the construction of institutional ambiance for elderly with Alzheimer's disease
Authors: Davim Barbara Stephane Canales , Bestetti Maria Luisa Trindade 
Published: December 2020

AbstractBackgroundThe process of institutionalization could lead to the loss of autonomy, individuality and familiarity for the elderly. (MACHADO, 2018). The possibility of decreasing functional capacity in the elderly requires new projects and constant adaptations in the built environment, furniture and objects. (PAIVA, SOBRAL & VILLAROUCO, 2016) Such as customized environments become more important as some areas of the brain stop working as they should, like in residents with Alzheimer's, who might feel lost and without a sense of self. (ZEISEL, 2006) Continuous environmental mementos contribute to the sense of belonging to a place, in more active processes of reminiscence and reimmersion. Each artifact might serve as a trigger to remembrance, contributing to the continuous sense of identity. (ROWLES, OSWALD & HUNTER, 2003).MethodA literature search was conducted in Ageline, Researchgate, Alzheimer's Association, SciVerse ScienceDirect and Google Scholar databases. A total of 30 items were reviewed, in the english or portuguese language, from 1983 to 2019.ResultIt urges the acknowledgment of personal objects for promotion and improvement of the relationship between the elderly diagnosed with Alzheimer's and the environment, although it lacks literature review focusing on recent empirical research in this area.ConclusionGiven that personal possessions could reinforce identity aspects, life achievements, attachments and important places, understanding this relationship could influence in improving social relations, higher environment‐related autonomy, and the maintenance of a more welcoming ambience. References: Machado, C. C. Avaliação dos Usuários Institucionalizados e não institucionalizados sobre Instituições de longa Permanência para Idosos na Cidade de Pelotas. Dissertação (Mestrado), Faculdade de Arquitetura e Urbanismo, Universidade Federal de Pelotas, 2018. Paiva, M. M.; Sobral, R. F. A.; Villarouco, V. Avaliação estética em ambientes residenciais de idosos, p. 293‐303. In: Anais do VI Encontro Nacional de Ergonomia do Ambiente Construído & VII Seminário Brasileiro de Acessibilidade Integral. São Paulo: Blucher, 2016. Rowles, G. D.; Oswald, Frank; Hunter, Elizabeth. Interior living environments in old age. Aging In Context: Sociophysical Environments: Annual Review of Gerontology and Geriatrics, Nova Iorque, v. 23, p.167‐194, jan. 2003. Zeisel, John. Inquiry by design: environment/behavior/neuroscience in architecture, interiors, landscape, and planning. New York: W. W. Norton; Revised edition, 2006.
Public health response to COVID‐19 for persons living with dementia in communities, acute care, and long‐term care settings
Authors: McGuire Lisa C , Shean John , French Molly 
Published: December 2020

AbstractBackgroundEmergencies and disasters can exacerbate or complicate unique vulnerabilities associated with dementia. The Healthy Brain Initiative’s State and Local Public Health Partnerships to Address Dementia: The 2018‐2023 Road Map calls for addressing the special needs of people with dementia and caregivers in emergency preparedness/response.MethodDuring the coronavirus (COVID‐19) pandemic, public health professionals play a critical role in protecting people living with dementia, their caregivers and families. The Alzheimer's Association and the Centers for Disease Control and Prevention (CDC) educated public health professionals and partners about the unique challenges associated with dementia during the pandemic and steps to tailor the emergency response. Homes in the community, acute care and long‐term care are three settings that require unique public health responses.ResultChallenges encountered vary by setting. In homes and the community, people living with dementia and their caregivers have been affected by the suspension of adult day services, social events, congregate meals, respite care, peer support groups, community education, physical activity classes and more, including virtual delivery of non‐urgent primary care, case management and behavioral health. Many emergency departments and hospitals adopted no‐visitor policies to reduce transmission of COVID‐19; however, caregivers for people living with dementia provide essential medical and emotional support that aids diagnosis and treatment. Long‐term care (LTC) facilities are especially prone to COVID‐19 outbreaks due to the concentration of vulnerable older adults, many with some form of cognitive impairment. Provision of person‐centered dementia care is hampered by no‐visitor policies without caregiver allowances and limited training of professionals working in LTC facilities during the crisis.ConclusionTaking immediate public health actions will not only help minimize the negative impacts of COVID‐19 on people living with dementia and their caregivers, but also support effective, efficient delivery of person‐centered care. Through this session, public health professionals will quickly learn about challenges posed by dementia in these settings, immediate steps to better protect health and safety for this population, and resources their departments can use. Disclaimer: The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the CDC.
Chronic health conditions in ethnic minority caregivers and the role of the acculturation
Authors: Hoang Diane , Nguyen Julia Phuong , Zhou Kieran , Harvey Danielle J , Meyer Oanh L 
Published: December 2020

AbstractBackgroundLittle is known about how the social and cultural context affects cardiovascular risk factors in Latino and Asian Americans. This study utilizes the California Health Interview Survey (CHIS) to examine how caregiving status and acculturation are related to chronic health conditions in a culturally diverse sample.MethodThe 2009 CHIS is a state‐wide representative dataset assessing health and health care of Californians. We examined whether acculturation [i.e., generational status (1st, 2nd, or 3rd) and language of interview (English or Spanish/Asian language)] as well as caregiving status were related to prevalence of hypertension, diabetes mellitus, and obesity, controlling for age, gender, marital status, income, self‐rated health, and neighborhood safety (N = 14,241).ResultThe sample was 58.3% Latino, 34.5% Asian, and 7.1% Multiracial. Caregivers had higher BMI than non‐caregivers (β=0.82, 95% CI=(0.17, 1.47), p=0.01). However, caregiving status was not associated with odds of having diabetes (OR=0.80, 95% CI: (0.54, 1.20), p=0.8) or hypertension (OR=1.18, 95% CI= (0.86, 1.62), p=0.3). Additionally, those interviewed in an Asian or Spanish language were less likely to be told they had diabetes (OR=0.56, 95% CI=(0.45, 0.69), p<0.001) or high blood pressure (OR=0.53, 95% CI=(0.42, 0.67), p<0.001) compared to those interviewed in English. Among all participants, 3rd generation individuals had a 75% increased odds of having high blood pressure (OR=1.75, 95% CI= (1.32, 2.34), p<0.001) compared to 1st generation individuals.ConclusionResults indicate that while caregivers had higher BMI, caregiving status was not related to hypertension or diabetes. Additionally, more acculturated individuals (as indicated by generational status and language of interview) were more likely to report being diagnosed with diabetes and hypertension. These results are consistent with the Healthy Immigrant Effect, which posits that immigrants who are more acculturated tend to have worse health, as they adopt the host country’s diet and health behaviors. Surprisingly, caregiving status (and potentially associated stress), was not related to hypertension or diabetes. Implications are discussed.
Investigating the role that astrocytes play in mediating changes in synaptic health in Alzheimer’s disease
Authors: Johnson Louisa , Noble Wendy , Perez‐Nievas Beatriz G 
Published: December 2020

AbstractBackgroundPrevious results from our group showed that abeta‐stimulated astrocytes release factors that are detrimental to neurons. Our aim is to investigate and validate those factors. One cytokine in particular is shown to be increased after treatment with low concentrations of oligomeric abeta and has been associated with abnormal tau cleavage. We analysed the effect of the cytokine on neuronal health and complexity and on localisation of tau. We also investigated whether the change in phenotype of astrocytes in response to abeta depends on abeta internalisation, and which pathways are involved.MethodPrimary astrocytic and neuronal cultures were prepared from CD1 mice following standard protocols. Neurons were treated with the cytokine and/or its receptor antagonist and transfected with GFP to allow measurement of dendritic spine density and neurite complexity. Localisation of tau was examined in similarly treated neurons by immunocytochemistry. To investigate abeta internalisation, transgenic conditioned media containing abeta was collected from Tg2576 neurons, with medium from littermate wild type neurons as a control. Astrocytes were treated with conditioned media in the presence or absence of Dynasore, a small molecule inhibitor of dynamin GTPases, and abeta uptake assessed by immunocytochemistry.ResultExposure of neurons to the cytokine results in a reduction of dendritic spine density and neuronal complexity which is rescued when its receptor is blocked by a specific inhibitor. Exposure to the cytokine also seems to affect tau localisation in neurons, causing mislocalisation of tau from the axonal to the somatodendritic compartment. Preliminary data shows that astrocytes internalise abeta quite quickly following addition to the medium, at least in part through endocytosis.ConclusionThe phenotype of astrocytes is altered in response to abeta, causing their secretion of molecules, including cytokines. Exposure of neurons to one of these cytokines causes reduced neuronal health and complexity, further confirming that factors released by astrocytes are synaptotoxic.
Urgent behavioral health phone calls from skilled nursing and long‐term care facilities during COVID‐19 lockdown
Authors: Posar Steven Laurence , Reid Anita , Heiser Daniel 
Published: December 2020

AbstractBackgroundBeginning the third week in March 2020 Skilled Nursing and Long‐Term Care Facilities (SNF‐LTC) in Indiana instituted protocols aimed at preventing the transmission of COVID‐19. These included exclusion of all visitors, room isolation and other measures. These measures were anticipated to have a deleterious effect on the mental health of SNF‐LTC residents. An Indiana neuro‐behavioral health practice (Vanguard Eldercare Medical Group), providing on‐site care at greater than 200 SNF‐LTC’s, measured the change in incoming urgent/emergent patient care phone requests during April as a potential proxy for a negative change in SNF‐LTC resident neuro‐psychiatric status.MethodUrgent/emergent incoming behavioral health phone requests were compiled from January 1, 2020 until May 17, 2020 on a weekly basis. Incoming calls during regular business hours (BH) (M‐F 7:00 AM to 5:00 PM) and after‐hours (AH) were measured from the medical group’s telephone monitoring system and EMR. These were analyzed using one‐tailed t‐tests to determine if the onset of the COVID‐19 pandemic (declared 3/11/2020) increased the number of incoming calls after accounting for the number of patients.ResultIn Figure 1, the number of BH calls appears to increase in the end of March, while AH calls appear to decline. Table 1 shows the mean number of BH calls per week prior to 3/9/2020 increases from 41.44 to 69.03 (p=0.0014). After hours calls decreased from 17.33 to 9.8 (p=0.00056) and the number of patients served increased from 7618.33 to 7767.90 (p=0.0073). To adjust for the increasing patient population, we calculated the mean number of calls per week per 1000 residents. BH calls per 1000 patients increased from 5.44 to 8.67 (p=0.0018) and AH calls per 1000 patients decreased from 2.28 to 1.26 (p=0.00052).ConclusionIt was anticipated that increased stressors would negatively impact these residents’ mental health. The significant increase in behavioral health phone requests suggests confirmation of this hypothesis. The disparity between business hours and after‐hours phone calls may be due to heightened SNF‐LTC staff awareness and/or change in the nature/severity of behavioral health decompensation.
A novel non‐toxic histone deacetylase inhibitor enhances spatial memory consolidation in male mice
Authors: Beamish Sarah B , Belayet Jawad B , Alanani Samer , Steeber Doug A , Hossain Mahmun M , Frick Karyn M 
Published: December 2020

AbstractBackgroundMemory dysfunction is a hallmark of Alzheimer’s disease (AD) and other dementias, yet truly effective treatments for memory loss do not exist. Memory dysfunction stems in part from reduced gene expression that leads to decreased levels of proteins essential for neural plasticity. Gene expression is facilitated by histone acetylation, an epigenetic mechanism that regulates chromatin accessibility. Compounds that maintain histone acetylation, called histone deacetylase inhibitors (HDACi), enhance memory by preventing deacetylation of core histone proteins, which allows for transcriptional machinery to bind open chromatin and increase gene expression. Although HDACi are promising therapeutics that could be used to prevent or delay memory loss associated with AD and other dementias, existing HDACi have poor solubility and undesirable toxicity. To address these shortcomings, our group has developed a novel HDACi compound, MJM‐1, that is brain‐penetrant and shows no evidence of toxicity. Here, we determine the extent to which MJM‐1can enhance memory.MethodsMale C57BL/6 mice were tested in object placement (OP) and object recognition (OR) tasks, which were used to assess spatial and object recognition memory consolidation, respectively. Mice received a post‐training intraperitoneal (i.p.) injection of either negative control (100% DMSO), positive HDACi control (sodium butyrate; 0.6 g/kg NaBu), or one of three doses of MJM‐1(20, 30, or 40 µg/g). During testing, one training object was moved to a new location in the open field (OP task) or was replaced with a novel object (OR task). Mice who remember the training objects should spend more time with the moved and/or novel objects.ResultsMice receiving NaBu, 20 µg/g MJM‐1, or 40 µg/g MJM‐1 spent significantly more time with the moved object, whereas DMSO‐treated controls mice did not, suggesting that the established HDACi NaBu and two doses of the novel HDACi MJM‐1 enhanced spatial memory consolidation. Mice receiving the 30 µg/g dose of MJM‐1 also tended to prefer the moved object. Conversely, none of the doses of MJM‐1 affected object recognition memory.ConclusionThe novel non‐toxic brain penetrant HDACi MJM‐1 can enhance spatial memory consolidation, suggesting encouraging proof of principle for future testing in models of aging and AD.
N‐terminal phosphorylation of Fused in Sarcoma (FUS) protein results in distinct changes to the cellular proteome that differ from the P525L model of pathology
Authors: Johnson Michelle A , Taylor Georgia L , Root Jessica , Kukar Thomas 
Published: December 2020

AbstractBackgroundFrontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) share many genetic and neuropathological markers of diseases (http://doi.org/10.1016/j.neuron.2013.07.033). One such neuropathological marker is the abnormal cytoplasmic aggregation of the Fused in Sarcoma (FUS) protein. FUS is a RNA/DNA binding protein involved in gene transcription, mRNA splicing, DNA‐repair pathways, and mRNA transport. To accomplish its many roles in the cell, FUS shuttles between the nucleus and cytoplasm carrying mRNA transcripts to distinct cellular locations. However, in FTD and ALS with FUS pathology, nuclear/cytoplasmic shuttling of FUS is disrupted resulting in its mislocalization into insoluble cytoplasmic inclusions (http://doi.org/10.1080/15476286.2016.1211225). Most pathological genetic mutations (including P525L) do not cause FTD (http://doi.org/10.1038/nn.3584). Therefore, non‐genetic factors such as post‐translational modifications may trigger FTD‐FUS pathology. Our lab discovered that double‐strand DNA damage induces phosphorylation of FUS (p‐FUS) at multiple N‐terminal sites leading to an accumulation of p‐FUS in the cytoplasm, yet the consequence of this cytoplasmic p‐FUS remain unknown (http://doi.org/10.1523/JNEUROSCI.0172‐14.2014). We set out to use an unbiased proximity labeling approach termed APEX2 to interrogate the WT FUS, P525L FUS, and p‐FUS proteomes.MethodWe and others have mapped the major N‐terminal phosphorylation sites, enabling the creation of a phosphomimetic variant of FUS (PM FUS) that mimics the phosphorylation of FUS caused by double‐stranded DNA damage. We then fused WT FUS, PM FUS, or P525L FUS to the engineered peroxidase, APEX2, and used proximity‐dependent biotin tagging to enrich for all proteins near the APEX2 complex. Biotin‐tagged proteins were identified and quantified using label‐free quantitative proteomics. Intensity readings were then corrected against controls using SAINT (Significance Analysis of INTeractome), a series of software tools that assign confidence values to observed protein‐protein interactions (http://doi.org/10.1038/nmeth.1541).ResultWe identified 3,313 differentially expressed proteins that were enriched in PM FUS, P525L FUS, and/or WT FUS over background. As expected, PM FUS enriched for cytoplasmic proteins as compared to WT FUS. Interestingly, the protein interactomes for PM FUS and P525L FUS separated independently of each other, suggesting distinct pathological mechanisms.ConclusionFindings from these studies will inform whether phosphorylation is a mechanism that could be targeted to shift FUS localization in FTD with FUS pathology.
Paradoxical cognitive reserve: Cognitive trajectories from earlier to later adulthood
Authors: Eglit Graham M.L. , Elman Jeremy A , Panizzon Matthew S. , Sanderson‐Cimino Mark E. , Williams McKenna E. , Dale Anders M. , Eyler Lisa T. , Fennema‐Notestine Christine , Gillespie Nathan A. , Gustavson Daniel E. , Hatton Sean N. , Hauger Richard L. , Jak Amy J. , Logue Mark W. , McEvoy Linda K. , McKenzie Ruth , Neale Michael C. , Puckett Olivia K. , Reynolds Chandra A. , Toomey Rosemary , Tu Xin M. , Whitsell Nathan , Xian Hong , Lyons Michael J. , Franz Carol E. , Kremen William S. 
Published: December 2020

AbstractBackgroundLongitudinal studies of aging are central to identifying early predictors of and mechanisms underlying late‐life cognitive decline and dementia. However, these studies typically lack cognitive data from earlier ages. It is therefore unclear how peak young adult general cognitive ability (GCA) and maintenance of GCA from young adulthood impact subsequent cognitive trajectories. To further understand GCA change from young adulthood, we evaluated whether poor GCA maintenance coincided with accelerated brain aging and was associated with key contributors to cognitive decline in later life, namely, aggregate vascular risk and Alzheimer’s disease polygenic risk (AD‐PRS).MethodIn the Vietnam Era Twin Study of Aging (VETSA), 1173 individuals were administered the same measure of GCA at average age 20 and at three VETSA waves beginning at average age 56. GCA maintenance scores were created by residualizing VETSA baseline GCA on age 20 GCA. Thus, good GCA maintenance was based on observed relative to expected scores. VETSA baseline GCA and GCA maintenance scores were entered into mixed effects models to predict specific cognitive abilities across three VETSA waves (∼6 years apart). Associations between GCA maintenance scores and indices of accelerated brain aging, aggregate vascular risk, and AD‐PRS were evaluated.ResultBetter GCA maintenance was associated with better VETSA baseline memory, semantic fluency, general fluency, processing speed, executive function, and working memory. However, given equivalent age 56 GCA, those who declined in GCA from age 20 outperformed those with stable GCA in memory, verbal fluency, executive function, and working memory at age 56. Thus, despite poor cognitive maintenance, some element of high peak cognitive reserve in early adulthood still confers benefit. All specific cognitive abilities declined over time, but neither VETSA baseline GCA nor GCA maintenance predicted extent of decline. Poor GCA maintenance from young adulthood was associated with accelerated brain aging and aggregate vascular risk, but not AD‐PRS.ConclusionBoth peak young adult GCA and GCA maintenance are important contributors to late midlife cognitive ability. Poor maintenance of GCA from young adulthood being associated with worse vascular health and coinciding with accelerated brain aging argues against a simple regression to the mean explanation.