bluuebunny/crossref_metadata_2025 huggingface dataset:
Rapidly progressive dementia in the COVID‐19 era
Authors: Dubey Shubham , Ramakrishnan V , Naveen P , Dubey Ayush
Published: December 2020

Background

Rapidly progressive dementias(RPD) are conditions that typically cause dementia over weeks or months.1 Due to the current COVID‐19 pandemic, it has become difficult for dementia caregivers on the one hand, and relevant detailed examination and management in the hospitals worldwide, on the other. Recent studies shows that ApoE e4 genotype is associated with both dementia and delirium2. Hence further research into the possible genetic link between dementia and COVID‐19 is the need of the hour.

Method

We studied two elderly male patients, aged 66 and 68 years, presenting with memory decline of recent events, untimely and non‐sequential Activities of Daily Living and apathetic alongwith way finding difficulty and errors in money transactions. One patient also had forgetfulness of handwashing and face hygiene measures, and of using preventive face masks in public places as advised for public health during COVID‐19 outbreak. On examination, vitals were stable and normal fundus examination with no fever, dry cough or tiredness, and no evidence of Increased Intracranial Pressure(ICP). MMSE score was 16/30 and 17/30 respectively, recent memory and visuospatial skills were impaired and slowness of activities were present. Motor examination was normal, with no focal or non‐focal neurological deficit or sensory impairment. All routine tests were normal. Neuroimaging with contrast in one patient showed well defined hyperdense mass lesion of size 4.0*3.5*3.0 cms. showing heterogenous contrast enhancement in left parieto‐occipital lobes with moderate perilesional edema suggestive of astrocytoma (intermediate type).

Result

High index of suspicion of Space occupying lesions should be made in the background of RPD even in the absence of focal or non focal neurological deficit or without signs of raised ICP.

Conclusion

Most of the etiologies causing RPD especially surgical causes, if diagnosed early and promptly are reversible and treatable. The double hit of dementia and COVID‐19 pandemic necessitates further research globally. References: 1) Paterson RW, Takada LT, Geschwind MD. Diagnosis and treatment of rapidly progressive dementias. Neurol Clin Pract. 2012;2(3):187–200. 2) Kuo C‐L, Pilling LC, Atkins JL, Kuchel GA, Melzer D. ApoE e2 and aging‐related outcomes in 379,000 UK Biobank participants. medRxiv [Internet]. 2020: 2020.02.12.20022459.
Genome‐wide association study of ADNI QT‐PAD biomarkers identifies a novel locus on Chr 12
Authors: Lee Brian N , Yao Xiaohui , Shen Li
Published: December 2020

Background

Identifying genetic basis of quantitative biomarkers in Alzheimer’s disease (AD) is a promising method to help deconvolute mechanistic complexity of AD and may lead to a better understanding of disease subtypes. Quantitative Templates for the Progression of Alzheimer’s disease (QT‐PAD, see http://www.pi4cs.org/qt‐pad‐challenge) provides a single, common and shared data freeze from Alzheimer’s Disease Neuroimaging Initiative (ADNI), including 16 imaging, cognitive and fluid AD biomarkers. To reveal novel AD genetic factors, we perform a genome‐wide association study (GWAS) of QT‐PAD biomarkers.

Method

Participants included 1,324 subjects from the ADNI QT‐PAD cohort with both biomarker concentration and genotyping data available. GWAS was performed to examine genetic associations between 565,373 SNPs (after going through a standard QC procedure) and concentrations of 16 key QT‐PAD biomarkers (see Figure 1), with age, gender, and education as covariates. GWAS was performed for both the baseline and m12 QT‐PAD data.

Results

We identified a novel locus rs5011804 on Chr 12 (baseline p =1.28E‐10, m12 p = 1.88E‐14) significantly associated with higher concentrations of biomarkers CDRSB, FAQ, and ADAS13 at both baseline and m12 visits (Figure 2), suggesting the variation (minor allele C) plays a role in affecting these three AD biomarkers. Figure 1 shows the complete GWAS findings at baseline using the genome‐wide significance threshold of p<5e‐8. This result not only affirms the key AD genes (APOE, TOMM40, PVRL2) but also suggests the promising role of rs5011804 due to its associations with seven QT‐PAD biomarkers. The SNP rs5011804 has a reported association with adult asthma (Vonk et al. 2017, PloS one, 12(3), e0172716) and slightly affects intracranial volume (corrected p = 0.05934) (Hibar et al. 2015, Nature, 520(7546), 224–229) but has not been associated with AD before.

Conclusion

QT‐PAD provides a standardized method for measuring the AD progression and allows for new quantitative genetics research. Genetic analysis of QT‐PAD biomarkers identified a novel locus in Chr 12 associated with multiple QT‐PAD biomarkers. The identified locus warrants further investigation in independent cohorts as a potential AD risk factor.
Depression and the apathy symptom are associated with poorer cognitive functioning in very old men
Authors: Guerrero‐Berroa Elizabeth , Schmeidler James , Phillips Ruby , Muallem Julia , Suleiman Halima , West Rebecca , Sano Mary , Reisberg Barry , Silverman Jeremy M
Published: December 2020

Background

Older adults (65+) are among the fastest growing segments of the population, projected to double by 2050. Oldest‐old (85+) manifest the greatest relative increase in population and have the greatest risk of developing Alzheimer’s Disease (AD). Depression is a chronic, debilitating condition in older adults. Depressive symptoms, particularly apathy—and poor concentration—have been associated with poor cognitive functioning and dementia. However, some associations depend upon gender, age of depression onset, and preexisting cognitive impairment; other studies find no association. Associations have been primarily in relatively young samples, and apathy has infrequently been studied in the very old. We investigated the cross‐sectional associations of depressive symptoms and apathy with cognitive functioning in cognitively normal very old men.

Methods

Participants consisted of 74 cognitively intact male veterans (age = 86 ±5.1 [mean ± SD], range = 76‐98; 81.1 % White, 18.9% Black; 15‐item Geriatric Depression Scale [GDS] = 2.6 ±2.7, range = 0‐12; 13.5% depressed [GDS ≥ 6]) enrolled in the Cardiovascular Risk Factors and Successful Cognitive Aging in Very Old Male Veterans study. The predictors were the GDS‐15 and the apathy item “Have you dropped many of your activities and interests?” Cognitive outcomes, from factor analysis of 11 neuropsychological test scores, were three Varimax factor cognitive domains (Episodic Memory, Attention, Executive Function), and the first principal component (global cognition). Linear regression analyses adjusted for age and education.

Results

Depressive symptoms were significantly associated with poorer global cognition (r = ‐.274, p = .020). Apathy was significantly associated with poorer Attention (r = ‐.403, p < .001) and global cognition (r = ‐.377, p = .001). Apathy remained significant after controlling for the sum of other depressive symptoms.

Conclusion

These results extend others’ findings by showing that depressive symptoms, and specifically apathy, are associated with poorer cognitive functioning in very old men. This study highlights the relevance of examining depressive symptoms as predictors of cognitive functioning. The small effect sizes (r ≤ .097) for memory, the hallmark cognitive symptom of AD, suggest possible non‐AD biological involvement. Future studies with larger and more demographically and ethnically diverse samples are warranted.
Metformin reduces behavioral, but not metabolic, disturbances associated with high‐fat diet
Authors: Jones Nahdia S , Rebeck G William
Published: December 2020

Background

APOE4 is the strongest genetic risk factor for Alzheimer’s Disease (AD), and obesity is a strong risk factor for developing dementia and cognitive disturbances. Metformin, the first line medication for Type II Diabetes, has been implicated in reducing metabolic and cognitive disturbances. Here we tested whether metformin ameliorated the disturbances associated with high fat diet (HFD) and whether metformin works equally on the APOE3 and APOE4 mice.

Method

Male and female human APOE3 and APOE4 knock‐in mice were fed either a HFD (45% kcal fat) or a low fat diet (LFD) (10% kcal fat) for 3 months (3 months‐6 months of age). During the last month of feeding, mice were given 300 mg/kg/day of metformin in drinking water. At the end of feeding, the following metabolic measurements were taken: weight, baseline glucose, and glucose tolerance. The mice were tested on the Open Field Test and Fear Conditioning apparatus.

Result

HFD induced a 30% increase in weight in male APOE3 mice and a 20% increase in male APOE4 mice. HFD also induced glucose intolerance in male APOE3 and APOE4 mice. Metformin did not reduce these metabolic disturbances. These metabolic disturbances were not seen in female mice on HFD. HFD decreased average speed and increased anxiety‐like behavior in APOE4 females on the open field test; metformin reduced these effects. With fear conditioning, there was a decrease in context based freezing behavior in female APOE3 mice on HFD, again with a metformin‐associated recovery. There were no behavioral effects of HFD on male mice.

Conclusion

HFD induced metabolic disturbances in male mice, but there were no differences between APOE genotypes and metformin did not reduce these metabolic disturbances. Furthermore, behavioral effects were only seen in female mice with metformin assisting in the rescue of these effects. The next step is to examine the alterations in the CNS due to HFD and metformin.
Effects of menopausal estrogen loss on the functional brain activity underlying associative memory
Authors: Brown Alana , Gervais Nicole J , Almey Anne , Duchesne Annie , Gravelsins Laura , Reuben Rebekah B , Baker‐Sullivan Elizabeth , Rieck Jenny , Baracchini Giulia , Foulkes William , Meschino Wendy , Grady Cheryl , Einstein Gillian
Published: December 2020

Background

Ovarian removal via bilateral salpingo‐oophorectomy (BSO) prior to spontaneous menopause (SM) is related to increased Alzheimer’s disease (AD) risk (Rocca et al., 2007). Associative learning deficits are considered the earliest AD symptoms, heralding preclinical AD (Fowler et al., 2002). Performance and brain activation during a face‐name associative memory task differ based on reproductive stage and are linked to fluctuating levels of 17β‐estradiol (E2; Rentz et al., 2017). We hypothesized that BSO would affect memory and functional brain activity during associative encoding.

Method

Middle‐age women underwent functional magnetic resonance imaging (fMRI) while completing a face‐name associative memory task (Sperling et al., 2003). Recognition performance and brain activation during face‐name pair encoding were assessed in women with BSO taking E2‐based hormone therapy (BSO+E2; n=10; mean age=46), women with BSO taking no hormone therapy (BSO; n=12; mean age=49), age‐matched women with intact ovaries (AMC; n=14; mean age=44), and older women in spontaneous menopause (SM; n=15; mean age=56).

Result

No group differences in face‐name pair recognition accuracy were found. Multivariate partial least squares analyses (McIntosh & Lobaugh, 2004) revealed significant differences in brain‐behaviour correlations between BSO and SM groups. Accuracy in the SM group correlated positively with activation of the hippocampus, medial temporal, parietal, and frontal lobes, while accuracy in the BSO group correlated negatively with activation of these regions (see Figure). Region‐of‐interest (ROI) analyses revealed that functional activity in the right superior frontal lobe correlated positively with E2 levels in the BSO+E2 group (r=0.83, p=0.01), and negatively with E2 levels in the BSO group (r=‐0.66, p=0.03).

Conclusion

Activation of distinct brain regions underlying associative memory depends on E2 and age. The BSO group, who experienced menopause approximately 10 years earlier than the SM group, showed significantly different patterns of brain activation compared to the SM group, ultimately to achieve similar recognition accuracy. Importantly, there were no significant differences in performance, indicating that brain changes may precede associative memory changes, and that E2 depletion could play an important role in brain activity underlying women’s associative memory.
The role of psychosocial factors in the formation of non‐cognitive symptoms of dementia
Authors: Sidenkova Alena Petrovna
Published: December 2020

Background

The non‐cognitive symptoms actualize a comprehensive medical and social study of dementia. The aim of the study is to study the psychosocial mechanisms of the formation of clinical, functional disorders in dementia, to develop comprehensive medical and psychosocial programs to help patients with dementia and those involved in caring for them, based on the proposals of the psychosocial model of dementia.

Method

A selective observational comparative dynamic study of 315 people with dementia of the Alzheimer's and 214 of the patients was carried out. The study used clinical, clinical, neuropsychological, sociometric, and statistical research methods.

Result

An increase in the severity of dementia contributes to a significant (p <0.05) increase in the number of patients in a dependent position in the family. The appearance of psychotic (painful ideas [r = 0.589]), behavioral (agitation / aggression [r = 0.654]), affective (anxiety [r = 0.536], unstable mood / irritability [r = 0.581]) symptoms of dementia contribute to family role changes structure and increase interpersonal distance in the dyad "caretaker ‐ patient." Those who provide unprofessional care for dementia patients in a statistically significant (p <0.05) majority of cases have a high level of emotional involvement in the care process. Changes in family‐role and social parameters, a high level of “expressed” emotions of caregivers have an adverse effect on the development of psychotic (r = 0.618), affective (r = 0.701), behavioral (r = 0.837) dementia disorders. The degree of adherence to anti‐dementia therapy by the caregiver is one of the important factors determining the amount of care received by the patient (r = 0.698). Agitation / aggression (r = 0.761), anxiety (r = 0.562), sleep disturbances (r = 0.521) contribute to increased compliance. The low satisfaction of the caregiver with premorbid (r = 0.698) and current (r = 0.653) relationships with the patient leads to a decrease in the compliance of the caregiver.

Conclusion

The formation of cognitive impairment is due to biological causes, their severity depends on the severity of dementia. The mechanism of psychopathological symptoms, functional disorders is heterogeneous depending on the biological causes and psychosocial conditions of functioning of patients.
Brain‐wide spatial analysis to identify region‐specific changes in cell composition associated with resilience to Alzheimer’s disease in the AD‐BXD mouse population
Authors: Gurdon Brianna , Hadad Niran , Telpoukhovskaia Maria , Yates Sharon , Puchades Maja Amedjkouh , Bjaalie Jan , Kaczorowski Catherine C
Published: December 2020

Background

Individual differences in brain structure have been associated with variation in brain atrophy and cognitive symptoms in Alzheimer’s disease (AD), but the underlying genetic mechanisms that dictate structural differences are not fully understood. Recent advances in large‐scale immunohistochemistry (IHC) now make it feasible to quantify region‐specific changes in cell composition and relate such changes to both clinically relevant traits (cognitive resilience) and gene expression for novel mechanistic insight.

Method

Forty hemibrains of adult and middle‐aged AD‐BXD strains, a translational mouse model of human AD, were stained to evaluate neurodegeneration (NeuN), gliosis (Iba1&GFAP), and AD‐specific pathology (AB1‐42) using IHC. Individual differences in cellular composition were quantified using % coverage of each stain across multiple brain regions obtained from the QUINT workflow, in which experimental slices were systematically segmented and registered to the Allen Brain Atlas Common Coordinate Framework. Cellular composition changes in hippocampus were then compared to bulk hippocampal gene expression levels to identify cellular and molecular correlates of resilience to AD.

Result

The % coverage of hippocampal GFAP+ astrocytes, Iba1+ microglia, and AB1‐42+ pathology increased with age and correlated with genes enriched for immune‐related pathways, chromatin remodeling, and mRNA processing. Neuronal cell load (% NeuN coverage) in the hippocampus of AD‐BXD mice was associated with genes enriched for GABA receptor activity, NMDA activation, extracellular matrix integrity, and autophagy. Moreover, in aged mice, genes positively correlated with NeuN coverage were enriched for cognition. This was further supported by the association between % NeuN coverage and improved cognition as measured by better performance on contextual fear memory tasks.

Conclusion

Using bulk RNAseq we were able to associate greater glial cell load with increased gene expression and explore pathways correlated with cellular composition in AD‐BXDs; however, it is unclear whether the variation in gene expression is a result of changes in the transcriptional activity of genes in these pathways, cell composition changes, or both. Integration of snRNAseq and brain‐wide quantitative maps will enable us to disentangle gene expression changes from cell composition, and perform genome‐wide studies to map the loci responsible for modulating these changes that underlie resilience in AD.
Drug prescription in elderly hospitalized patients with cognitive impairment in the Italian dementia‐friendly hospital project
Authors: Govoni Stefano , Rosi Alessia , Preda Stefania , Allegri Nicola
Published: December 2020

Background

Older patients with cognitive impairment represent a significant proportion of the patients hospitalized for various acute illnesses. The health staff is not prepared to deal with such patients which do not fit the standard of care of the hospital stay. Accordingly, we recorded a series of clinical parameters reflecting the health status and the drug prescriptions at the entry and during hospital stay before and after a brief (5 hrs. frontal teaching) intervention of staff training, focusing on improving the management of patients with cognitive impairment.

Methods

Participants were evaluated within 48 h of admission and at discharge with Mini Mental State Examination (MMSE), Barthel Index, Instrumental Activity of Daily Life (IADL), and Hospital Anxiety and Depression Scale (HADS). A preliminary analysis of 68 hospitalized participants aged 65 and older with cognitive impairment (MMSE ≥ 16, ≤24) allocated in the control group (n = 34, 20 females, 82.38 years) and intervention group (n = 34, 20 females, 81.97 years) was performed. For each patient, the number of prescriptions, sedative and anticholinergic load, and drug–drug interactions were evaluated.

Results

Participants presented a widespread polypharmacy receiving as average 6.9 (+/‐ 1.7 drugs/daily in the control group) and 5.9 (+/‐ 1.6 drugs/daily in the intervention group), the difference being not statistically significant (P = 0,068). Also, the sedative load presented a trend toward lower values in the intervention group. The results concerning the other clinical indices (submitted elsewhere) show that personnel training significantly improved the functional and anxiety parameters at discharge.

Conclusions

The results suggest that an intervention, focused on improving dementia care practices in health staff, having the potential to improve outcomes for hospitalized older adults with cognitive impairment, but not directly designed to manage drug polypharmacy, is not sufficient to modify drug prescription patterns.
Inhibition of human islet amyloid polypeptide aggregation and cellular toxicity by oleuropein and derivatives from olive oil
Authors: Chaari Ali
Published: December 2020

Background

Beta‐cell death is the key feature of type 2 diabetes mellitus (T2DM). One hypothesis for the mechanism of this feature is amyloid formation by the human Islet Amyloid Polypeptide (hIAPP). Clinical trials and population studies indicate the healthy virtues of the Mediterranean diet, especially the extra virgin olive oil (EVOO) found in this diet. This oil is enriched in phenolic compounds shown to be effective against several aging and lifestyle diseases. Oleuropein (Ole), one of the most abundant polyphenols in EVOO, has been reported to be anti‐diabetic.

Method

I report here a broad biophysical approach and cell biology techniques that enabled me to characterize the different molecular mechanisms by which tyrosol (TYR), hydroxytyrosol (HT), oleuropein (Ole) and oleuropein aglycone (OleA) modulate the hIAPP fibrillation in vitro and their effects on cell cytotoxicity.

Result

OleA was found to be more active than Ole, HT and TYR at low micromolar concentrations. I further demonstrated that comparing to other used polyphenols, OleA inhibits the cytotoxicity induced by hIAPP aggregates by protecting more the cell membrane from permeabilization and then from death.

Conclusion

These findings highlight the benefits of consuming EVOO and the great potential of its polyphenols. Moreover, they support the possible pharmacological use of EVOO polyphenols for T2DM prevention and therapy as well as for many other amyloid‐related diseases.
Single‐cell RNA sequencing analysis for common molecular signatures of microvascular injury
Authors: Guo Xinying , Zhao Zhen
Published: December 2020

Background

Mild Traumatic brain injury (mTBI) is a significant risk factor for Alzheimer’s disease (AD). Given that microvascular injury is common and persistent following mild TBI and that neurodegeneration is a late consequence following some TBIs, vascular dysfunction may be an important link between mTBI and AD. However, little attention has been focused on how the cerebral vasculature responds following mTBI induced AD. The goal of our work is to evaluate the potential common molecular signatures in cerebral microvessels in conditions such as mTBI, AD affected, and aging using single‐cell RNA sequence (sc‐RNA seq) approach.

Method

The processed single‐cell gene UMI count information from the study of single‐cell sequencing was collected for the secondary analysis using the newest R Seurat Package. Cell count matrix from different groups were integrated using a new method, which is to identify ‘anchors’ across diverse single cell data types in order to transfer information accurately across experiments. After integration, the vasculature cells are taken for another round of clustering to reveal heterogeneity within the vasculature cell. This subsetting of the data enabled us to highlight more subtle changes within the vasculature cell and uncover the unique change which is masked because of few vessel cells.

Result

Through analyzing vascular cells from the sc‐RNA seq data of mTBI dataset and aging dataset, we found differential expression genes of endothelial cells from two datasets, and discovered that microvascular injury is related to the damage of extracellular matrix, metabolic crisis, transport barrier dysfunction, protein refolding, blood flow, signaling, and changes of binding between molecules.

Conclusion

Single cell genomics provides unique information about how mTBI and aging impacts diverse cell types, adding new insights into the pathogenic pathways amenable to therapeutics in mTBI induced late‐onset Alzheimer’s disease. Therapeutic approaches against microvessel injury will have important implications for future treatment of AD and other neurodegenerative diseases.
Blood flow improvement trial: Design and enrollment
Authors: MacAlpine Maiya F , Heston Margo B , Gaitán Julian M , Okonkwo Ozioma C , Bendlin Barbara B , Gretebeck Kimberlee A , Gretebeck Randall J
Published: December 2020

Background

Midlife insulin resistance (IR) has previously been shown to be associated with lower cerebral blood flow (CBF), and is a potentially modifiable risk factor for dementia. The Blood Flow Improvement Trial (BFiT), NCT03117829 , tested a 12 week carbohydrate restricted diet (CRD) and exercise behavioral intervention to reverse IR, and aimed to 1) determine the extent to which improving or normalizing glucose homeostasis improves CBF and cognitive function in individuals with IR, 2) determine whether participants continue to maintain improved or normalized glycemic control for 6 months, and 3) determine changes in the human metabolome as individuals improve or normalize IR and glucose homeostasis through diet and exercise.

Method

Participants were recruited from the Wisconsin Alzheimer’s Disease Research Center and screened for metabolic risk factor eligibility based on the criteria shown in Table 1. The design involved a 12 week diet and exercise intervention focused on self‐monitoring to promote adherence. Exercise was conducted in a supervised group setting 3 days/week for 50 minutes and participants were instructed to exercise on their own an additional 2 days/week. Participants followed a CRD and monitored their own blood glucose with the goal of achieving and maintaining fasting blood glucose <100 mg/dL. Participants underwent baseline, 12 week, and 6 month procedures including urine and blood labs/metabolomics, cognitive testing, fitness testing, and blood flow imaging via MRI (Table 2).

Result

The enrollment goal was 40 participants. 118 individuals were screened for eligibility, and 72.5% of the target enrollment was met; of those participants, nearly 80% completed the 12 week intervention. Of the 23 participants that completed the intervention, mean attendance was 70% for supervised exercise sessions and 81% for weekly behavioral coaching sessions. Figure 1 summarizes screening, enrollment, and procedure completion.

Conclusion

IR may be a modifiable risk factor for dementia. The BFiT pilot trial was designed to test the feasibility of exercise and CRD to reduce IR and improve brain blood flow in middle‐aged adults. Reasonable enrollment and completion N were achieved. Future analysis will center on barriers to enrollment and adherence, as well as analysis of the primary and secondary outcome measures.
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

Background

Development 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.

Method

Six 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.

Result

Variability 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.

Conclusion

Proteomic 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

Background

The 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).

Method

A 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.

Result

It 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.

Conclusion

Given 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

Background

Emergencies 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.

Method

During 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.

Result

Challenges 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.

Conclusion

Taking 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

Background

Little 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.

Method

The 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).

Result

The 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.

Conclusion

Results 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

Background

Previous 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.

Method

Primary 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.

Result

Exposure 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.

Conclusion

The 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

Background

Beginning 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.

Method

Urgent/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.

Result

In 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).

Conclusion

It 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

Background

Memory 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.

Methods

Male 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.

Results

Mice 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.

Conclusion

The 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

Background

Frontotemporal 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.

Method

We 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).

Result

We 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.

Conclusion

Findings from these studies will inform whether phosphorylation is a mechanism that could be targeted to shift FUS localization in FTD with FUS pathology.