bluuebunny/crossref_metadata_2025 huggingface dataset:
Predicting mechanisms of action at genetic loci associated with discordant effects on type 2 diabetes and abdominal fat accumulation
Authors: Aberra Yonathan Tamrat , Ma Lijiang , Björkegren Johan LM , Civelek Mete
Published: June 2023

Metabolic syndrome (MetSyn) is a cluster of dysregulated metabolic conditions that occur together to increase the risk for cardiometabolic disorders such as type 2 diabetes (T2D). One key condition associated with MetSyn, abdominal obesity, is measured by computing the ratio of waist-to-hip circumference adjusted for the body-mass index (WHRadjBMI). WHRadjBMI and T2D are complex traits with genetic and environmental components, which has enabled genome-wide association studies (GWAS) to identify hundreds of loci associated with both. Statistical genetics analyses of these GWAS have predicted that WHRadjBMI is a strong causal risk factor of T2D and that these traits share genetic architecture at many loci. To date, no variants have been described that are simultaneously associated with protection from T2D but with increased abdominal obesity. Here, we used colocalization analysis to identify genetic variants with a shared association for T2D and abdominal obesity. This analysis revealed the presence of five loci associated with discordant effects on T2D and abdominal obesity. The alleles of the lead genetic variants in these loci that were protective against T2D were also associated with increased abdominal obesity. We further used publicly available expression, epigenomic, and genetic regulatory data to predict the effector genes (eGenes) and functional tissues at the 2p21, 5q21.1, and 19q13.11 loci. We also computed the correlation between the subcutaneous adipose tissue (SAT) expression of predicted effector genes (eGenes) with metabolic phenotypes and adipogenesis. We proposed a model to resolve the discordant effects at the 5q21.1 locus. We find that eGenes gypsy retrotransposon integrase 1 (GIN1), diphosphoinositol pentakisphosphate kinase 2 (PPIP5K2), and peptidylglycine alpha-amidating monooxygenase (PAM) represent the likely causal eGenes at the 5q21.1 locus. Taken together, these results are the first to describe a potential mechanism through which a genetic variant can confer increased abdominal obesity but protection from T2D risk. Understanding precisely how and which genetic variants confer increased risk for MetSyn will develop the basic science needed to design novel therapeutics for metabolic syndrome.
Ribozyme activity modulates the physical properties of RNA–peptide coacervates
Authors: Le Vay Kristian Kyle , Salibi Elia , Ghosh Basusree , Tang TY Dora , Mutschler Hannes
Published: June 2023

Condensed coacervate phases are now understood to be important features of modern cell biology, as well as valuable protocellular models in origin-of-life studies and synthetic biology. In each of these fields, the development of model systems with varied and tuneable material properties is of great importance for replicating properties of life. Here, we develop a ligase ribozyme system capable of concatenating short RNA fragments into long chains. Our results show that the formation of coacervate microdroplets with the ligase ribozyme and poly(L-lysine) enhances ribozyme rate and yield, which in turn increases the length of the anionic polymer component of the system and imparts specific physical properties to the droplets. Droplets containing active ribozyme sequences resist growth, do not wet or spread on unpassivated surfaces, and exhibit reduced transfer of RNA between droplets when compared to controls containing inactive sequences. These altered behaviours, which stem from RNA sequence and catalytic activity, constitute a specific phenotype and potential fitness advantage, opening the door to selection and evolution experiments based on a genotype–phenotype linkage.
Application of public emotion feature extraction algorithm based on social media communication in public opinion analysis of natural disasters
Authors: Li Shanshan , Sun Xiaoling
Published: June 2023

Natural disasters are usually sudden and unpredictable, so it is too difficult to infer them. Reducing the impact of sudden natural disasters on the economy and society is a very effective method to control public opinion about disasters and reconstruct them after disasters through social media. Thus, we propose a public sentiment feature extraction method by social media transmission to realize the intelligent analysis of natural disaster public opinion. Firstly, we offer a public opinion analysis method based on emotional features, which uses feature extraction and Transformer technology to perceive the sentiment in public opinion samples. Then, the extracted features are used to identify the public emotions intelligently, and the collection of public emotions in natural disasters is realized. Finally, through the collected emotional information, the public’s demands and needs in natural disasters are obtained, and the natural disaster public opinion analysis system based on social media communication is realized. Experiments demonstrate that our algorithm can identify the category of public opinion on natural disasters with an accuracy of 90.54%. In addition, our natural disaster public opinion analysis system can deconstruct the current situation of natural disasters from point to point and grasp the disaster situation in real-time.
Physiologic effects of surgical masking in children versus adults
Authors: Brooks J Patrick , Layman Jill , Willis Jessica
Published: June 2023

Background

Surgical masks remain a focal part of the CDC guidelines to decrease COVID-19 transmission. Evidence refuting significant effects of masking on ventilation is mostly limited to small studies, with a paucity of studies on children, and none comparing children to adults.

Methods

A total of 119 subjects were enrolled (71 adults, 49 children) in a prospective interventional study with each subject serving as their own mask-free control. End tidal CO2 (ETCO2), inspired CO2 (ICO2), and respiratory rate were measured by nasal cannula attached to an anesthesia machine D-fend module. Pulse oximetry and heart rate were also followed. After the mask-free period, an ASTM Level 3 disposable surgical mask was donned and 15 min of mask-worn data were collected.

Results

A steady state was confirmed for ETCO2 and ICO2 over the masked period, and mean ICO2 levels rose significantly (p < 0.001) after masking in all age groups. The increase in ICO2 for the 2- to 7-year-old group of 4.11 mmHg (3.23–4.99), was significantly higher (p < 0.001) than the final ΔICO2 levels for both the 7- to 14-year-old group, 2.45 mmHg (1.79–3.12), and adults, 1.47 mmHg (1.18–1.76). For the pediatric group there was a negative, significant correlation between age and ΔICO2, r = −0.49, p < 0.001. Masking resulted in a statistically significant (p < 0.01) rise in ETCO2 levels of 1.30 mmHg in adults and 1.36 mmHg in children. The final respective ETCO2 levels, 34.35 (33.55–35.15) and 35.07 (34.13–36.01), remained within normal limits. Pulse oximetry, heart rate, and respiratory rate were not significantly affected.

Discussion

The physiology of mechanical dead space is discussed, including the inverse relationship of subject age vs ICO2. The methodology and results are compared to previously published studies which detracted from the physiologic safety of surgical masking.

Conclusions

The wearing of a surgical mask results in a statistically significant rise in ICO2 and a smaller rise in ETCO2. Because ETCO2 and other variables remain well within normal limits, these changes are clinically insignificant.
Inverse Hamza Distribution: Properties and Applications to Lifetime Data
Authors: Frank Okpala I. , Obiora-Ilouno Happiness O. , Frederick Omoruyi A.
Published: June 2023

In this paper, a new distribution, named ‘the Inverted Hamza distribution’, was introduced.  It is an extension of the Hamza distribution that can model real-world data with an upside-down bathtub shape and heavy tails.  Mathematical and statistical characteristics such as the quantile function, moments, entropy measure, stochastic ordering and distribution of order statistics have been derived. Furthermore, dependability measures such as the survival function and hazard function have been developed. The greatest likelihood technique was used to estimate the distribution parameters. To demonstrate the applicability of the distribution, a numerical example was given. According on the results, the proposed distribution outperformed the competing distributions.
Role of Cytokinin Oxidase/ Dehydrogenase in Crop Improvement
Authors: Yadav Ankit , Pratibha  , Sonagara Mayur Kumar , Vaghela Unnati
Published: June 2023

The phytohormone cytokinin regulates various crucial functions of plant growth and development such as shoot apical meristem activity, flower development, vascular development etc. and also has negative role in lateral root development and root apical meristem activity. Cytokinin is degraded by cytokinin oxidase/dehydrogenase (CKX) irreversibly and reversible inactivation by glucosylation. Various homologous genes of CKX have been identified in Arabidopsis and in many other crop plants. The root specific expression of CKX showed positive results for larger root with higher lateral root numbers and higher root to shoot biomass. The site-specific manipulation of CKX gene has been done in crops like wheat, barley, maize, rice, legumes and horticultural crops to regulate the cytokinin levels in the particular tissues to enhance the yield, tolerance to various abiotic stresses (drought, salt, lower soil fertility), biofortification for many micronutrients (Zn, Fe) in the seed, propagation, etc. And the use of modern techniques in manipulation of CKX have been started to improve the crop plant and the outcome is very promising for the future application in commercial agricultural activities.
Application of WOA-Based LSSVM Model for Wind Speed Prediction in Mianyang, China
Authors: Yang Yiqi , Zhang Longfeng , He Xin
Published: June 2023

In recent years, countries have vigorously developed renewable energy resources to alleviate energy shortages and improve the environment. Wind energy, as a clean and renewable new energy source, has been increasing its power generation capacity, but the wind power generation itself has the characteristics of volatility and instability which makes wind power generation more difficult. Therefore, a novel prediction model based on the least squares support vector machine (LSSVM) with whale optimization algorithm (WOA) is proposed in the paper to improve the prediction accuracy and applied to the wind speed prediction in Mianyang. The model is implemented in python language, and then the prediction results are then evaluated quantitatively using the mean absolute percentage error (MAPE), and the results of the proposed model are compared with models such as eXtreme Gradient Boosting (XGBoost), Support Vector Regression (SVR) and Random Forest (RF). Further, the MAPE of the prediction results of the proposed model is about 4.7%-5.5%, which can be 6.3% higher than other models at best. The results show that the proposed prediction model can have good prediction accuracy and generalization performance and can be applied to other fields in the future.
For Health Equity, We Must End Mass Incarceration
Authors: Wang Emily A. , Shavit Shira
Published: June 2023

This Viewpoint discusses the health harms to individuals and communities because of mass incarceration in the US and proposes interventions to ensure health equity for all individuals.
Medicare Modernization—The Urgent Need for Fiscal Solvency
Authors: Miller Brian J. , Grabert Lisa M. , Hargan Eric D.
Published: June 2023

This Viewpoint describes how reforms to Medicare built around a transition from volume to value may be helpful for improving fiscal solvency.
Spherical Lithium Deposition Enables High Li‐Utilization Rate, Low Negative/Positive Ratio, and High Energy Density in Lithium Metal Batteries
Authors: Wang Caoyu , Yang Chunpeng , Du Yahao , Guo Zaiping , Ye Huan
Published: June 2023

Lithium metal battery promises an attractively high energy density. A high Li‐utilization rate of Li metal anode is the prerequisite for the high energy density and avoiding a huge waste of the Li resource. However, the dendritic Li deposition gives rise to “dead Li” and parasitic interfacial reactions, resulting in a low Li utilization rate. Herein, Li deposition is regulated to spherical Li by designing an MXene host with an egg‐box structure, suitable curvature, and continuous gradient lithiophilic structure. Because the spherical Li greatly reduces the interfacial side reactions and avoids the formation of dead Li, the Li anode affords a high plating/stripping efficiency. Furthermore, the gradient lithiophilic design results in a bottom‐up growth of the spherical Li within the host, safely away from the separator. Thus, the spherical Li anode realizes a long life of >3000 h with a high Li‐utilization rate of >90%, stable cycling in full cells at an areal capacity up to 5 mAh cm−2 with a low negative/positive ratio of 0.8, which is critical for high energy density. Such spherical deposition highlights the critical role of the morphological control of alkali metals and provides a viable method to build practical high‐energy metal batteries.
Artificial Spider Silk with Buckled Sheath by Nano‐Pulley Combing
Authors: Sun Jinkun , Guo Wenjin , Mei Guangkai , Wang Songli , Wen Kai , Wang Meilin , Feng Danyang , Qian Dong , Zhu Meifang , Zhou Xiang , Liu Zunfeng
Published: June 2023

The axial orientation of molecular chains always results in an increase in fiber strength and a decrease in toughness. Here, taking inspiration from the skin structure, artificial spider silk with a buckled sheath–core structure is developed, with mechanical strength and toughness reaching 1.61 GPa and 466 MJ m−3, respectively, exceeding those of Caerostris darwini silk. The buckled structure is achieved by nano‐pulley combing of polyrotaxane hydrogel fibers through cyclic stretch–release training, which exhibits axial alignment of the polymer chains in the fiber core and buckling in the fiber sheath. The artificial spider silk also exhibits excellent supercontraction behavior, achieving a work capacity of 1.89 kJ kg−1, and an actuation stroke of 82%. This work provides a new strategy for designing high‐performance and intelligent fiber materials.
Exploring the Potential of Three‐Dimensional DNA Crystals in Nanotechnology: Design, Optimization, and Applications
Authors: Kong Huating , Sun Bo , Yu Feng , Wang Qisheng , Xia Kai , Jiang Dawei
Published: June 2023

DNA has been used as a robust material for the building of a variety of nanoscale structures and devices owing to its unique properties. Structural DNA nanotechnology has reported a wide range of applications including computing, photonics, synthetic biology, biosensing, bioimaging, and therapeutic delivery, among others. Nevertheless, the foundational goal of structural DNA nanotechnology is exploiting DNA molecules to build three‐dimensional crystals as periodic molecular scaffolds to precisely align, obtain, or collect desired guest molecules. Over the past 30 years, a series of 3D DNA crystals have been rationally designed and developed. This review aims to showcase various 3D DNA crystals, their design, optimization, applications, and the crystallization conditions utilized. Additionally, the history of nucleic acid crystallography and potential future directions for 3D DNA crystals in the era of nanotechnology are discussed.
Preparation and specific adsorption of dual antibacterial BSA surface imprinted GO‐PEI/MXene wrinkled microspheres
Authors: Li Yulong , Lyu Yanting , Yang Zuoting , Wang Ting , Zhang Qiuyu , Zhang Baoliang
Published: June 2023

Molecular imprinting technology has gained increasing attention and application in protein adsorption and separation. Bacterial growth on the imprinted material would reduce the adsorption selectivity and shorten the service life. To solve the above problems, carrier materials (GO‐PEI/MXene wrinkled microspheres) with dual antibacterial ability are constructed for the first time. BSA surface imprinted GO‐PEI/MXene (GO‐PEI/MXene@MIPs) are constructed in this study. The large exterior surface area increases the number of imprinting sites, thereby enhancing the adsorption capacity. The adsorption capacity of GO‐PEI/MXene@MIPs reaches 312.63 ± 22 mg/g with an imprinting factor (IF) of 3.15 within 90 min. Meanwhile, GO‐PEI/MXene@MIPs can separate BSA from mixed protein solution and fetal bovine serum (FBS) and only loses 14.1% of saturation adsorption after eight cycles. In addition, antibacterial tests show that the material has excellent broad‐spectrum antibacterial effects, which will significantly extend the service life of the material in real‐world environments.
K‐doped CuO/ZnO with dual active centers of synergism for highly efficient dimethyl carbonate synthesis
Authors: Han Han , Ye Xue , Yao Jie , Gao Xinhua , Yu Jinghao , Guo Lisheng , Li Jie
Published: June 2023

The application of heterogeneous catalysts in dimethyl carbonate (DMC) synthesis from methanol is hindered by low activation efficiency of methanol to methoxy intermediates (CH3O*), which is the key intermediate for DMC generation. Herein, a catalyst of alkali metal K anchored on the CuO/ZnO oxide is rationally designed for offering Lewis acid–base pairs as dual active centers to improve the activation efficiency of methanol. Characterizations of CO2‐TPD, NH3‐TPD, XPS, and DRIFTS revealed that the addition of Lewis base K observably boosted the dissociation of methanol and combined with Lewis acid CuO/ZnO oxide to adsorb the formed CH3O* stably, thus synergistically promoted the transesterification. Finally, the CuO/ZnO‐9%K2O catalyst exhibited the optimal catalytic activity, achieving a high yield of 74.4% with an excellent selectivity of 98.9% for DMC at a low temperature of 90°C. The strategy of constructing Lewis acid–base pairs provides a reference for the design of heterogeneous catalysts.
Identification of brain aging subtypes in multiple brain regions from cognitively normal individuals
Authors: Peng Shouneng , Haure‐Mirande Jean‐Vianney , Wang Minghui , Huffman Derek M , Haroutunian Vahram , Ehrlich Michelle E. , Zhang Bin , Tu Zhidong
Published: June 2023

Background

Although late‐onset Alzheimer’s disease (LOAD) occurs in older individuals (age 65 or older), multiple lines of evidence suggests that the dysregulation of brain functions initiates decades earlier. Through examining multiple large‐scale human brain transcriptomic data, we demonstrated that cognitively normal brain aging from donors in their 40s‐60s can group into several subtypes based on their hippocampal transcriptomes. One subtype represents healthy brain aging and some evidence suggests these donors may remain cognitively normal in much older ages, while some brain aging subtypes showed gene expression changes highly similar to those observed in AD, supporting molecular changes linked to AD have occurred much earlier than the manifestation of cognitive impairment. However, whether the brain aging subtype is a common phenomenon across multiple brain regions or very specific to the hippocampus remains unknown.

Method

We compiled and studied transcriptomic data in another commonly studied human brain region (prefrontal cortex) from donors who were cognitively normal. We performed hierarchical clustering in these samples to infer subtypes, differential gene expression analysis was done between samples from different subtypes. We annotated and compared these DEGs with other AD gene expression signatures.

Result

We discovered that aging subtypes could also be observed in the prefrontal cortical region. Similarly to the hippocampus, the differentially expressed genes among aging subtypes also highly overlapped with AD gene signatures. By comparing aging subtypes defined from hippocampal vs. cortical transcriptomes from the same individuals, we found that an AD similar hippocampal sample does not necessarily correspond to AD similar cortical sample in the same donor, suggesting the brain regional complexity of the disease.

Conclusion

Our analysis of the transcriptomic data from multiple brain regions from cognitively normal individual supports that gene regulation changes related to AD occurs decades earlier than the manifestation of clinical phenotype. Understanding the molecular changes in these early changes in multiple brain regions could be critical to gain new insights into the mechanisms of AD initiation.
Novel c.2654+1G>A mutation in the CSF1R gene in a family with CSF1R‐microglial encephalopathy
Authors: Jiang Jiwei , Xu Jun
Published: June 2023

Background

The colony‐stimulating factor‐1 receptor (CSF1R) is a transmembrane tyrosine kinase receptor that is mainly expressed in the brain‐resident microglia. Thus, microglial dysfunction due to CSF1R mutation may play a primary and pivotal role in the pathogenesis of CSF1R‐microglial encephalopathy. Neither the functional consequences of all known CSF1R mutations nor the full genetic spectrum of mutations causing CSF1R‐microglial encephalopathy have been fully elucidated. We aimed to describe a novel heterozygous splicing variant of the CSF1R gene that caused CSF1R‐microglial encephalopathy in a Han Chinese family.

Method

The demographic data, detailed medical history, and clinical manifestations were collected from a family with CSF1R‐microglial encephalopathy. Some family members also underwent neuropsychological evaluation, structural and functional magnetic resonance imaging (MRI), and whole‐exome sequence analyses.

Result

Four generations of this family, including 27 members, presented with a medical history of a dominant hereditary pattern (Figure 1). Seven of these 27 individuals had died, while five presented with similar cognitive impairments clinically, including the proband, and his sister, father, uncle, and grandmother during their life. Brain MRI of the proband (Figure 2) and his sister (Figure 3) depicted symmetric confluent and diffuse deep white matter changes, atrophy of the frontoparietal lobes, and thinning of the corpus callosum. The brother of the proband remained asymptomatic, and the structural brain MRI only revealed minimal white matter changes; however, pseudo‐continuous arterial spin labeling (pCASL) demonstrated marked reduction in the cerebral blood flow (CBF) in the bilateral deep white matter and corpus callosum (Figure 4). Whole‐exome sequencing was performed for seven family members, which identified a novel splice‐site heterozygous mutation (c.2319+1C>A) in intron 20 of the CSF1R gene in four members (Figure 5).

Conclusion

We identified a novel splicing mutation (c.2319+1C>A) in intron 20 of CSF1R as the cause of CSF1R‐microglial encephalopathy in a Han Chinese family, which broadens the genetic spectrum of CSF1R‐microglial encephalopathy. We opine that clinically feasible pCASL techniques may be more sensitive to the alterations in CBF of associated with microglial density and cellular changes. This study highlights the potential value of pCASL techniques to improve the clinical diagnostic accuracy of CSF1R‐microglial encephalopathy.
Neuropsychiatric syndromes in Alzheimer’s disease: Systematic review and meta‐analysis of the factor structure of the neuropsychiatric inventory
Authors: Hiu Shaun , Bigirumurame Theophile , Kunonga Patience , Bryant Andrew , Pillai Manjunadh
Published: June 2023

Background

Neuropsychiatric symptoms (NPS) are a prevalent feature in patients with Alzheimer’s disease (AD). Studies have consistently observed that certain NPS have a tendency to co‐occur with others. One major focus of NPS research has been to understand the factor structure of the Neuropsychiatric Inventory (NPI) to identify neuropsychiatric syndromes in AD. Whilst there is a large literature of studies, there exists heterogeneity in the results derived.

Method

We sought to increase our certainty about how neuropsychiatric syndromes in AD may be defined by conducting a systematic review and meta‐analysis of the literature from 1994‐2020 regarding the factor structure of the NPI. We used meta‐analytic structural equation modelling (MASEM) to pool effect sizes (correlation coefficients between NPI items) under a random effects model and fitted measurement models from published studies to identify a best‐fitting factor structure.

Result

Twenty‐four studies met our eligibility criteria however effect sizes were only available for seven studies. For the NPI‐10 (7 studies, n = 5185), a five‐factor structure was found to have good fit to the data across a majority of model fit indices (CFI = 0.966; TLI = 0.940; SRMR 0.031; RMSEA 0.026 [95% CI 0.021, 0.030]). For the NPI‐12 (4 studies, n = 2397), we were unable to identify a factor structure that displayed good model fit.

Conclusion

Our meta‐analysis indicated that a five‐factor structure to the NPI‐10 – agitation, irritability, and aberrant motor behaviour (factor 1); delusions and hallucinations (factor 2); depression and anxiety (factor 3); euphoria and disinhibition (factor 4); and apathy (factor 5) – was the best‐fitting measurement model.
Study of the mechanism of action of Blarcamesine (ANAVEX®2‐73): Whole blood transcriptomics analysis identifies treatment impact on compensatory pathways by restoring key neurodegenerative pathways functionality, including Alzheimer’s disease pathway
Authors: Williams Coralie , Kindermans Martin , Parmentier Frédéric , Goodsaid Federico , Hammond Edward , Missling Christopher U , Afshar Mohammad
Published: June 2023

Background

Blarcamesine (ANAVEX®2‐73), a novel oral selective sigma‐1 receptor (SIGMAR1) agonist was investigated in a clinical Phase 2a study in Alzheimer’s disease in which blarcamesine resulted in a lower rate of cognitive (MMSE) and functional (ADCS‐ADL) decline. Following the positive results of this study, a translational approach led to investigating blarcamesine in an international, double‐blind, multicenter, placebo‐controlled Phase 2 clinical study of 14‐week duration in 132 patients with Parkinson’s disease dementia (PDD). Whole blood transcriptomics analysis (RNAseq) was performed for the PDD study at two timepoints: baseline and Week 14. After quality control filtering, 14,150 genes were retained for analysis.

Methods

Weighted gene correlation network analysis (WGCNA) was used to identify clusters of genes that show a correlated expression change across patients and timepoints. Thus, a data‐driven gene network was generated. Associations between the identified clusters and treatment arms were explored in order to select clusters for which gene expression is significantly associated with the high blarcamesine dose. These associations were assessed using linear mixed effect models with three covariates: dose, patient and timepoint. Significance was assessed with Dunett’s test.

Results

Blarcamesine significantly restores functionality in key pathways of Alzheimer’s disease, Parkinson’s disease and Prion diseases. The analysis identified two clusters of genes that are significantly differentially expressed in treated patients and represent compensatory pathways to genes dysregulations induced by neurodegenerative diseases. In both clusters, majority of genes were confirmed to interact (STRING database). Amongst interacting genes, neurodegenerative pathways were identified as overrepresented (p < 0.01). Down‐regulation of genes involved with neurodegeneration was observed in the placebo arm, however, was compensated in the blarcamesine arm.

Conclusions

This analysis identified a gene network that is differentially expressed in patients treated with blarcamesine after 14 weeks of treatment, compared to placebo. The biological relevance of this gene network was assessed. Pathway analysis confirmed the impact of the treatment on pathways involved in neurodegenerative diseases The identification of a gene network as the blarcamesine response pathway lays the foundation to better understand the mechanism of action at the molecular level of blarcamesine, thus unlocking characterization of responders based on molecular profiling, as well as identification of new indications in the area of neurodegenerative and other disorders.
Social networks of neighbourhood inhabitants, residents of a care facility, and the nursing staff: a case study in two LTF facilities in the Netherlands
Authors: van Beek Sandra , Groenewegen Peter , Portegijs Suzanne , Huygens Martine , Volker Beate
Published: June 2023

Background

Social resources have the potential to relieve the pressure on long‐term care facilities due to population ageing and staff shortages. This is because social networks can constitute the link between residents, staff members of LTC facilities and members of the local community. In this paper we describe these social networks and the relationships of which they consist in two LTC facilities that provide dementia care in the Netherlands, thereby illustrating the social capital of both facilities.

Methods

Staff members of the dementia ward in two LTC facilities, family members of residents and inhabitants of the neighbourhoods surrounding the LTC facilities were asked to complete questionnaires.

Results

There are direct and indirect relationships between nursing staff, family members of residents and inhabitants of the neighbourhood. Staff know residents both directly, and indirectly through connections with other persons in the community. There is regular contact between staff members and family members of residents during visits of family members; one third of nursing staff also talk to family members outside the LTC facility. Furthermore, staff members often live close to the facility and are therefore connected to inhabitants of the neighbourhood. About half of the neighbourhood inhabitants visited the LTC facility during the past 12 months for various reasons. More than half of the neighbourhood inhabitants know persons that work in the LTC facility, one in five knows a staff member working on the dementia ward. In total, 8% of the neighbourhood inhabitants in our study worked as a volunteer in the LTC facilities.

Conclusion

The network of the LTC facilities’ staff, residents with dementia, and local community consists of many direct and indirect relationships. Although it is difficult for residents with dementia to uphold their social networks, there are numerous ties that demonstrate the pre‐existing social relationships of persons with dementia in the community that can be employed to provide person‐centred care. The embeddedness of LTC facilities can also be considered as a resource in finding and retaining personnel and volunteers, as most of the staff live in the neighbourhood and volunteers are often in close proximity.
Excitability and glymphatic function in an animal model of Alzheimer’s disease
Authors: Müller Luisa , Kirschstein Timo , Köhling Rüdiger , Deike‐Hoffmann Katerina , Radbruch Alexander , Kuhla Angela , Teipel Stefan
Published: June 2023

Background

APPswe/PS1dE9 mice reproduce features of amyloid β (Aβ) pathology and neuronal dysfunction as reflected in electrophysiological recordings of neuronal hyperexcitability. This leads to changes in sleep‐wake‐rhythm, downstream affecting brain clearance functionality. Our objective is to investigate the effect of circadian rhythm and Aβ pathology on clearance efficacy in APPswe/PS1dE9 mice.

Method

First, we examined the brain wide distribution of an intrahippocampal injected fluorescent dye. Dye was injected at 6 am (post wake period) or 6 pm (post sleep period) and sampled 1 or 3 h post injection for histological analysis (Figure 1A) in n = 3 transgenic mice and n = 3 non‐transgenic mice per group. Secondly, in an in vivo approach we analyzed the brain wide distribution of a gadolinium based contrast agent using a T2‐RARE sequence in a 7 Tesla small animal MRI scanner (Bruker BioSpin GmbH, Germany) (Figure 1B) in n = 4 transgenic mice and n = 4 non‐transgenic mice. We measured values for brightness in manually defined regions of interest with PMOD software (version 3.7; PMOD Technologies LLC, Switzerland).

Result

In the first experiment, we were able to observe dye distribution in the brain parenchyma as surrogate for interstitial clearance net flux. Preliminary results point to an effect of circadian rhythm, as a trend of better dye distribution shortly after the sleep period was observed. Furthermore, a possible detrimental effect of the Aβ phenotype on clearance was observed in transgenic mice. In comparison to non‐transgenic mice they showed a trend of lesser dye distribution independent of day‐time. With the second approach, we were able to observe influx and efflux of applied contrast agent into cerebrospinal fluid. Preliminary data point to a trend of an increased slope of the influx as well as decreased slope of the efflux in transgenic mice.

Conclusion

Histological analysis of a stereotactic injected dye is a feasible method for investigation of dye distribution outlining a possible effect of daytime and amyloid pathology. However, MR‐imaging is a promising tool as we will be able to observe the disease progression in mice longitudinally. Further experiments will be needed to ensure these preliminary results and maybe also point to underlying mechanistic basis.
Homocysteine altered gyrification related to self‐awareness of everyday cognition
Authors: Wang Ziqi , Dong LI , Cai Qingyan , Jian Wei , Yao Dezhong
Published: June 2023

Background

Previous studies on homocysteine have verified higher homocysteine may adversely influence cognition performance in individuals with subjective cognitive decline (SCD), whereas the potential mechanisms for this relationship are still unclear.

Method

We analyzed data from 23 individuals with SCD enrolled in the 500 nm light therapy cohort who filled the 12 items Everyday Cognition scale (ECog‐12) and had plasma homocysteine levels assessed at the time of their baseline 3T MRI scans. Gyrification and cortical thickness were obtained by using whole brain region of interest (ROI)‐based approach with the CAT12 toolbox (in SPM12). Statistical analyses used one‐sample t‐test including age and sex as covariates. Regions of significant group effects were used as regions of interest for cognitive performance analyses.

Result

At corrected thresholds (p < 0.05, Holm‐Bonferroni‐corrected), there were significant negative correlations between homocysteine and gyrification in the left temporal pole (p = 0.012000) and right inferior temporal sulcus (p = 0.012268). For cortical thickness, we found a significant positive correlation of homocysteine and cortical thickness in the right inferior temporal sulcus (p = 0.032744). In addition, a significant positive correlation was found between the self‐report ECog‐12 scores and gyrification of the left temporal pole.

Conclusion

Homocysteine alters local surface shape in temporal lobule in SCD patients and localized low gyrification may imply impaired self‐awareness of everyday cognition.
Centiloid scale measure of amyloid PET by CT‐guided anatomic standardization
Authors: Matsuda Hiroshi , Hanyu Haruo , Kaneko Chikako
Published: June 2023

Background

Centiloid (CL) scaling has become a standardized quantitative measure in amyloid PET because it facilitates the direct comparison of results across institutions, even when different analytical methods or tracers are used. Standard volumes of interest must be used to calculate the CL scale after the anatomic standardization of amyloid PET images using coregistered MRI; if the MRI is unavailable, the CL scale cannot be accurately calculated. This study sought to determine the substitutability of CT, which is used to correct PET attenuation in PET/CT equipment, by evaluating the measurement accuracy when CT is used as an alternative to MRI in the calculation of the CL scale.

Method

Amyloid PET images obtained using 11C‐PiB from 19 patients with possible or probable Alzheimer’s disease were processed to calculate the CL scale using 3D T1‐weighted MRI (Optima MR450w, 1.5T, GE healthcare) and CT of PET/CT (uMI780, United Imaging Healthcare). CLMRI and CLCT were respectively defined as the use of MRI and CT for anatomic standardization and compared. We followed the method advocated by the Global Alzheimer’s Association Interactive Network for the calculation of the CL scale. The whole cerebellum was chosen as a reference area for the CL calculation.

Result

A Bland–Altman plot showed that CLCT did not significantly differ from CLMRI (mean ± standard deviation, −0.1 ± 1.5; p = 0.734). The 95% limits of agreement ranged from −0.8 to 0.6. Pearson correlation analysis showed a highly significant correlation of r = 0.999 between CLCT and CLMRI (p < 0.001). The linear regression equation was CLCT = 0.992 × CLMRI + 0.144. In a Bland–Altman plot, Spearman correlation analysis did not identify a significant association between the difference in CLMRI versus CLCT and CL load (ρ = −0.045, p = 0.853).

Conclusion

CL scales based on CT show a highly significant positive correlation with those based on MRI, regardless of the degree of amyloid accumulation in possible and probable AD patients. A key advantage of the use of CT is the simultaneous acquisition of PET and CT. This method would be applicable to subjects who are unable to undergo MRI.
Apolipoprotein E4 impairs iron efflux in human induced pluripotent stem cell (iPSC)‐derived cortical neurons by reducing ferroportin on cell surface
Authors: Xu He , Gao Huiling
Published: June 2023

Background

Iron homeostasis disturbance has been implicated in Alzheimer’s disease (AD), and excess iron exacerbates oxidative damage and cognitive defects. Ferroportin (Fpn) is the only known iron exporter and the expression of Fpn is decreased in the brains of AD patients. Apolipoprotein E (APOE) gene is the most important genetic risk factor for late‐onset AD. The three common proteins encoded by the gene are ApoE2, ApoE3, and ApoE4. They bind to iron with different affinities, which mediates the isoform‐specific antioxidant activity. However, whether ApoE takes part in neuronal iron homeostasis remains unclear.

Method

Cortical neurons were generated from human iPSCs (All from non‐demented APOE3/E3 carriers). The intracellular iron content was measured using inductively coupled plasma mass spectrometry (ICP‐MS) after co‐treatment of iron and ApoE. Western blot analysis was performed to examine the alterations of various iron storage and transport proteins. Cell surface Fpn expression levels were measured by fluorescence‐activated cell sorting (FACS).

Result

Intracellular iron level in ApoE4‐treated neurons was higher than that in ApoE2‐ or ApoE3‐treated neurons. Furthermore, Fpn level on cell surface was reduced by ApoE4 treatment.

Conclusion

Our study demonstrates that ApoE4 impairs iron efflux and exacerbate iron accumulation via regulating surface Fpn level.
Aquaporin 4 is associated with cerebral amyloid‐beta and tau deposits in mouse models
Authors: Kecheliev Vasil , Maschio Cinzia , Konetiko Uwe , Nitsch Roger M. , Klohs Jan , Ni Ruiqing
Published: June 2023

Background

Emerging evidence indicates that the glymphatic system plays an important role in Alzheimer’s disease. Aquaporin 4 (AQP4) constitutes a critical part of the glymphatic system in the clearance of accumulated amyloid‐beta and tau from the brain. Here, we aimed to establish the association between AQP4 and tau as well as amyloid‐beta (Aβ).

Method

Perfusion and susceptibility weighted imaging (SWI) magnetic resonance imaging (MRI, at 7 or 9.4 T) were performed in arcAβ mouse model of amyloidosis (aged 16‐18 months), P301L mouse model of 4‐repeat tau (pR5 line) and respective nontransgenic littermates (aged 10‐12 months). Immunofluorescence staining was performed using antibodies against AQP4, CD31, astrogliosis (GFAP, s100β), microgliosis (Iba1, CD68), Aβ (6E10), and tau (AT‐8 and AT‐100) in brain tissue slices from transgenic arcAβ mice and wild‐type littermates.

Result

Cerebral microbleeds were detected in the cortex and subcortical regions in arcAβ mice. Cerebral blood flow was reduced in the cortex and hippocampus of arcAβ compared to nontransgenic mice but preserved in P301L mice. Increased AQP4 levels were observed surrounding tau deposits in the forebrain of P301L mice and parenchymal amyloid plaques/cerebral amyloid angiopathy in the cortex and hippocampus of arcAβ mice. Depolarization of AQP4 was detected in both arcAβ and P301L mice compared to their respective nontransgenic littermates. Increased s100b‐GFAP and CD68‐Iba1 fluorescence intensities indicative of atrogliosis and microgliosis were detected around tau deposits in P301L mice and amyloid plaques in arcAβ mice.

Conclusion

We observed impaired perfusion in arcAβ mice but not in P301L mice, and a spatial association of AQP4 with both tau and Aβ in the brain.
Ophthalmic pathology in patients with primary neurodegenerative diseases
Authors: Makhnovich Ekaterina Vladimirovna , Bogolepova Anna Nicolaevna , Andreevna Kovalenko Ekaterina , Alekseevna Osinovskaya Nina
Published: June 2023

Background

The priority problem of modern healthcare is irreversible dementia due to the steady increase in morbidity. Among irreversible dementias, Alzheimer’s disease takes the first place. Most often, only with sufficiently pronounced cognitive disorders, the doctor can diagnose Alzheimer’s disease, although it is obvious that the neurodegenerative process begins even before the clinical manifestations of the disease. Due to the common origin of the eye and the brain, we can say that the eye is a “window to the brain”. Many scientists note the similarities between gerontophthalmological diseases and Alzheimer’s disease.

Method

The study examined 60 patients who were divided into 2 groups: the first group included patients with Alzheimer’s disease, the second group included patients with vascular dementia. Each group included 9 men and 21 women, with an average age of 65.5 years. All patients underwent a comprehensive neuropsychological examination, using the short Mental Status Assessment Scale (MMSE), the Montreal Cognitive Function Assessment Scale (MoCA), the battery of tests for assessing frontal dysfunction (FAB), the clock drawing test. Also, all patients underwent ophthalmological examination of the visometry, measurement of intraocular pressure, examination of the anterior segment of the eye and fundus, and spectral optical coherence tomography.

Result

In the course of the study, significant ophthalmic pathology was detected in the group with neurodegenerative changes ‐ age‐related macular degeneration was found in 16.7%, pseudoexfoliative syndrome‐20%, primary open‐angle glaucoma‐46.7%.

Conclusion

This means that the risk of developing gerontophthalmological diseases increases in patients with neurodegenerative disorders. Therefore, we can assume that the retina is a mirror of neurodegenerative changes in the brain, which will allow to diagnose the disease at early stages and with the help of drug therapy to delay further development of the disease, resulting in reduced disability for patients and socio‐economic costs of society.

The results obtained are promising for the early diagnosis of primary neurodegenerative diseases and indicate the need for further research on this topic.
Using Academic Detailing to enhance the knowledge, skills and attitudes of clinicians caring for patients with behavioral and psychological symptoms of dementia: 18‐month follow‐up
Authors: Walaszek Art , Schroeder Molly , Albrecht Tammi , LeCaire Tamara J. , Carlsson Cynthia M.
Published: June 2023

Background

Approximately 90% of persons with dementia experience behavioral and psychological symptoms of dementia (BPSD) over the course of their illness. Primary care clinicians often provide care because specialty geriatric psychiatry consultation may be difficult to obtain. Academic detailing (AD) is an evidence‐based approach for engaging and persuading healthcare professionals to make changes in their practice. We sought to enhance the knowledge, skills and attitudes of primary care providers’ care of patients with BPSD using the AD model.

Methods

We implemented AD in an urban clinic serving a largely Black community and a rural clinic serving a largely White community. Each AD visit included didactic content, case discussion, and consultation regarding patients. Eleven visits over 18 months were planned for each site. Outcome measures included a 10‐item multiple‐choice knowledge assessment and an adaptation of the General Practitioners Attitude and Confidence Scale for Dementia at baseline, 6 and 18 months, and Likert‐scale measurement of acceptability at 6 and 18 months, all self‐report. Differences in knowledge and attitude scores were determined for those providing complete responses at baseline and follow‐up. Thematic analysis of qualitative feedback collected 18 months will be completed.

Results

Five urban and 14 rural providers completed baseline assessments. Providers were mostly White (95%) and Non‐Hispanic (100%); 47% were female (Table 1). Seventeen (89%) participated in one or more AD visits and 13 (68%) participated in the 6‐month survey. Knowledge, attitudes and confidence regarding BPSD and dementia care increased (Table 2). Assessments at 18‐months and qualitative analysis of case discussions are forthcoming and will be presented.

Conclusions

Academic detailing (AD) is a feasible way of increasing self‐reported knowledge and skills and improving self‐reported attitudes of primary care providers responsible for the care of patients with BPSD. Knowledge and confidence in BPSD and dementia care increased after 6 months’ participation in AD. During the pandemic we successfully adapted the AD model to a virtual platform, which has implications for portability of this model to other settings. The pilot data collected in this study will inform the design of a larger study to measure the impact of AD on patient outcomes.
Amyloid PET ordering practices in a memory disorders clinic
Authors: Turk Katherine W , Vives‐Rodriguez Ana , Schiloski Kylie A , Marin Anna , Wang Ryan , Singh Prabhjyot , Hajos Gabor P , Powsner Rachel , DeCaro Renee , Budson Andrew E
Published: June 2023

Background

The objective of the current study was to assess amyloid PET scan ordering practices in a Veterans Affairs memory disorders clinic, where such scans are readily available, and the extent to which amyloid PET ordering may occur in memory disorders clinics if covered by insurance in the future.

Methods

Using retrospective chart review over a three‐year period, we compared patient demographic, clinical, and MRI structural features that were predictive of ordering an amyloid PET scan in a memory disorders clinic to those of patients who did not have one ordered. The percentage of patients who met previously published appropriate use criteria were evaluated.

Result

Overall 34.9% of patients received an amyloid PET scan as part of their diagnostic workup and 97.9% of these ordered scans were consistent with appropriate use criteria. Patients who received an amyloid PET were younger on average and more likely to have an initial diagnosis of suspected AD. Overall, 64.4% of patients without an amyloid PET scan ordered would have met appropriate use criteria for amyloid PET. Thus, fewer patients received an amyloid PET scan than were eligible according to current appropriate use criteria.

Conclusion

A little more than a third of veterans in a memory disorders clinic received an amyloid PET scan as part of their diagnostic work up when ordering was freely available to cognitive behavioral neurologists and not constrained by third‐party reimbursement. The vast majority of amyloid PET scans ordered were consistent with current appropriate use criteria. Future versions of the appropriate use criteria for amyloid PET could address ordering in patients with subjective cognitive decline with behavioral/functional impairments as well as patients under consideration for possible anti‐amyloid therapy treatment with Aducanumab and other medications in this class.