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Fibrillar amyloidosis and synaptic vesicle protein expression progress jointly in the cortex of a mouse model with β-amyloid pathology
Get PDFNeurodegeneration, accumulation of β-amyloid (Aβ) plaques, and neuroinflammation are the major hallmarks of Alzheimer's disease. Here, we aimed to investigate the temporal and spatial association between synaptic activity, Aβ plaque load, and neuroinflammation in an Aβ mouse model with limited neurodegeneration.
26 APPSL70 and 15 C57Bl/6 mice underwent longitudinal PET-scans with [18F]UCB-H from plaque onset to levels of strong plaque load (5.3 - 11.0 months of age) to assess the synaptic vesicle protein 2A (SV2A) expression, [18F]FBB to determine the fibrillar Aβ plaque load, and [18F]GE-180 and [18F]F-DED to assess microglial and astroglial (re)activity. Statistical parametric mapping was performed to uncover similarities between the binding patterns of all four tracers.
We found a continuous increase in Aβ-PET in APPSL70 mice from 5.3 to 11.0 months of age, resulting in a significantly higher [18F]FBB PET signal in the cortex, hippocampus, and thalamus of APPSL70 mice compared to C57Bl/6 mice at 11.0 months of age. Parallel increases in SV2A-PET signals were observed in the cortex and thalamus of APPSL70 mice compared to C57Bl/6 mice. Statistical parametric mapping revealed a similar pattern of Aβ- and SV2A-PET differences (dice coefficient 53 %). Patterns of microglia activation showed stronger congruency with SV2A expression (dice coefficient 58 %) than patterns of reactive astrogliosis (dice coefficient 26 %).
APPSL70 mice with limited neurodegeneration comprise a close temporal and spatial association between SV2A expression, Aβ plaque load, and microglial activation. SV2A PET imaging in APPSL70 mice may facilitate longitudinal monitoring of increased synaptic activity in the earliest phase of AD
Early increase of the synaptic blood marker β‐synuclein in asymptomatic autosomal dominant Alzheimer's disease
Get PDFIntroduction: β-synuclein is a promising blood marker to track synaptic degeneration in Alzheimer's disease (AD) but changes in preclinical AD are unclear.
Methods: We investigated serum β-synuclein in 69 cognitively unimpaired mutation non-carriers, 78 cognitively unimpaired AD mutation carriers (asymptomatic AD), and 31 symptomatic mutation carriers from the Dominantly Inherited Alzheimer Network.
Results: β-synuclein levels were already higher in asymptomatic AD mutation carriers compared to non-carriers and highest in symptomatic carriers. Longitudinal trajectories and correlation analyses indicated that β-synuclein levels start to rise after amyloid deposition preceding axonal degeneration, brain atrophy and hypometabolism, and cognitive decline. β-synuclein levels were associated with cognitive impairment and gradually increased with declining cognition.
Discussion: Our study supports the use of blood β-synuclein to track synaptic changes in preclinical AD and as a surrogate marker for cognitive impairment which might be used in early diagnosis and to support patient selection and monitoring of treatment effects in clinical trials
Correction of dysregulated lipid metabolism normalizes gene expression in oligodendrocytes and prolongs lifespan in female poly-GA C9orf72 mice
Get PDFClinical and genetic research links altered cholesterol metabolism with ALS development and progression, yet pinpointing specific pathomechanisms remain challenging. We investigated how cholesterol dysmetabolism interacts with protein aggregation, demyelination, and neuronal loss in ALS. Bulk RNAseq transcriptomics showed decreased cholesterol biosynthesis and increased cholesterol export in ALS mouse models (GA-Nes, GA-Camk2a GA-CFP, rNLS8) and patient samples (spinal cord), suggesting an adaptive response to cholesterol overload. Consequently, we assessed the efficacy of the cholesterol-binding drug 2-hydroxypropyl-β-cyclodextrin (CD) in a fast-progressing C9orf72 ALS mouse model with extensive poly-GA expression and myelination deficits. CD treatment normalized cholesteryl ester levels, lowered neurofilament light chain levels, and prolonged lifespan in female but not male GA-Nes mice, without impacting poly-GA aggregates. Single nucleus transcriptomics indicated that CD primarily affected oligodendrocytes, significantly restored myelin gene expression, increased density of myelinated axons, inhibited the disease-associated oligodendrocyte response, and downregulated the lipid-associated genes Plin4 and ApoD. These results suggest that reducing excess free cholesterol in the CNS could be a viable ALS treatment strategy
Nitride Zeolites from Ammonothermal Synthesis
Get PDFOxide zeolites are synthesized from aqueous solutions in an established way employing hydrothermal synthesis. Transferring this approach to nitride zeolites requires a solvent providing nitrogen for which ammonia has proven to be particularly suitable. We present the successful ammonothermal synthesis of the (oxo)nitridosilicate compounds Ce3[Si6N11], Li2RE4[Si4N8]O3 (RE=La, Ce) and K1.25Ce7.75[Si11N21O2]O0.75. Within this procedure, the usage of supercritical ammonia as a solvent as well as the utilization of the mineralizers NaN3, Li3N and KN3, respectively, allowed the targeted synthesis of large single crystals. Formation of these (oxo)nitridosilicates depends mainly on the employed mineralizer despite their similar degree of condensation. The three compounds were structurally characterized using X-ray diffraction and their crystal structures contain a wide range of different ring sizes within their tetrahedra networks. The zeolite(-like) crystal structures are elucidated and compared to known nitridosilicate representatives of the respective structure types. Their elemental composition was investigated using energy-dispersive X-ray (EDX) spectroscopy and incorporation of the O rather than N−H functionality was confirmed by Fourier-Transform infrared (FTIR) spectroscopy as well as by charge distribution (CHARDI) and bond valence sum (BVS) calculations. The presented examples demonstrate that ammonothermal synthesis provides a one-step access from elemental starting materials towards nitride zeolites
P2X7R antagonism suppresses long-lasting brain hyperexcitability following traumatic brain injury in mice
Get PDFPurpose: Post-traumatic epilepsy (PTE) is one of the most common life-quality reducing consequences of traumatic brain injury (TBI). However, to date there are no pharmacological approaches to predict or to prevent the development of PTE. The P2X7 receptor (P2X7R) is a cationic ATP-dependent membrane channel that is expressed throughout the brain. While increasing evidence suggests a role for the P2X7R during seizures and epilepsy, it is unclear if changes in P2X7R expression can predict TBI-induced epilepsy development, and whether P2X7R antagonism can protect against long-lasting brain hyperexcitability caused by TBI.
Methods: TBI was induced in adult male mice using the controlled cortical impact model (CCI). To test the anti-epileptogenic effects of P2X7R antagonism, mice were treated with brain-penetrant P2X7R antagonists JNJ-54175446 (30 mg/kg) or AFC-5128 (30 mg/kg) for 7 days post-CCI. The cell-type specific effects of P2X7Rs on TBI-induced hyperexcitability were analyzed in mice lacking exon 2 of the P2rx7 gene selectively in microglia (P2rx7:Cx3cr1-Cre). Static positron emission tomography (PET) via an intravenous injection of the P2X7R radioligand 18F-JNJ-64413739 and magnetic resonance imaging (MRI) were conducted twice during the first- and third-week post-injury.
Results: Following TBI, while there were no obvious changes in P2X7R protein levels in the ipsilateral hippocampus post-injury, there was a delayed increase in P2X7R protein levels in the ipsilateral cortex at 3 months post-injury. Treatment with P2X7R antagonists shortly after TBI reduced long-lasting brain hyperexcitability, reduced cortical contusion volume, and normalized injury-induced hyperactivity to control sham-levels at 3 weeks post-TBI. Notably, mice lacking P2rx7 in microglia had an increased seizure threshold after TBI, suggesting that P2X7R contributed to brain hyperexcitability via its effects on microglia. Finally, P2X7R radioligand uptake after TBI correlated with seizure threshold at 3 weeks post-injury.
Conclusions: Our results demonstrate the antiepileptogenic potential of P2X7R antagonism to prevent TBI-induced epilepsy and indicate that P2X7R-based PET imaging may be a useful diagnostic tool to identify people at risk of developing PTE
Multilayered social media self-presentation practices : How German adolescents present themselves on Instagram and Snapchat
Get PDFSelf-presentation plays a significant role during adolescence and is often performed on image-based social media plat forms, such as Instagram and Snapchat. Our study examined common self-presentation practices and overarching forms of self-presentation among German adolescents as well as the influence of both individual (gender, social media use, per ceived benefits) and structural influencing factors (audience size and anticipated feedback) on these forms of selfpresentation. We conducted computer-assisted face-to-face surveys with 1,002 German Instagram and/or Snapchat users between 14 and 16 years of age. Our findings illustrate that adolescents present themselves through a variety of different practices on Instagram and Snapchat. We identified selfpresentation practices that are common on both platforms, but we also found indications for platform-specific practices. Furthermore, principal component analysis identified three overarching forms of self-presentation: staged selfpresentation, authentic self-presentation, and presentation of everyday life
Targeting the isoprenoid pathway in choleste biosynthesis: An approach to identify isoprenoid biosynthesis inhibitors
Get PDFThe development of novel cholesterol biosynthesis inhibitors is a task of major concern due to the diverse roles of cholesterol and its precursors in physiological processes. Therefore, appropriate screening assays are required, which can be used to identify and quantify specific inhibitors targeting the desired enzyme. Here, we developed a whole-cell screening assay based on a HL60 cell line, which can be used to characterize inhibitors interacting with enzymes of the isoprenoid part of cholesterol biosynthesis. Due to the change of the isoprenoid pattern under enzyme inhibition, an identification of the targeted enzyme is possible. With the described assay, we can distinguish between free and pyrophosphorylated isoprenoids after enzymatic cleavage in cellular and extracellular matrices. The approach was validated in line with the European Medicines Agency guideline on bioanalytical method validation. As proof of concept, literature-described inhibitors of the isoprenoid pathway were tested. We characterized the effect of 11 isoprenoid biosynthesis inhibitors, and we identified 6-fluoromevalonate as an isopentenyl pyrophosphate isomerase inhibitor, a biological activity that was previously unknown. Furthermore, isoprenoid patterns revealed that, independent of the analyzed matrix, the predominant form of the detected isoprenoids were dephosphorylated isoprenoids and only small amounts were present as pyrophosphates
Practical applications of methods to incorporate patient preferences into medical decision models: a scoping review
Get PDFBackground
Algorithms and models increasingly support clinical and shared decision-making. However, they may be limited in effectiveness, accuracy, acceptance, and comprehensibility if they fail to consider patient preferences. Addressing this gap requires exploring methods to integrate patient preferences into model-based clinical decision-making.
Objectives
This scoping review aimed to identify and map applications of computational methods for incorporating patient preferences into individualized medical decision models and to report on the types of models where these methods are applied.
Inclusion Criteria
This review includes articles without restriction on publication date or language, focusing on practical applications. It examines the integration of patient preferences in models for individualized clinical decision-making, drawing on diverse sources, including both white and gray literature, for comprehensive insights.
Methods
Following the Joanna Briggs Institute (JBI) methodology, a comprehensive search was conducted across databases such as PubMed, Web of Science, ACM Digital Library, IEEE Xplore, Cochrane Library, OpenGrey, National Technical Reports Library, and the first 20 pages of Google Scholar. Keywords related to patient preferences, medical models, decision-making, and software tools guided the search strategy. Data extraction and analysis followed the JBI framework, with an explorative analysis.
Results
From 7074 identified and 7023 screened articles, 45 publications on specific applications were reviewed, revealing significant heterogeneity in incorporating patient preferences into decision-making tools. Clinical applications primarily target neoplasms and circulatory diseases, using methods like Multi-Criteria Decision Analysis (MCDA) and statistical models, often combining approaches. Studies show that incorporating patient preferences can significantly impact treatment decisions, underscoring the need for shared and personalized decision-making.
Conclusion
This scoping review highlights a wide range of approaches for integrating patient preferences into medical decision models, underscoring a critical gap in the use of cohesive frameworks that could enhance consistency and clinician acceptance. While the flexibility of current methods supports tailored applications, the limited use of existing frameworks constrains their potential. This gap, coupled with minimal focus on clinician and patient engagement, hinders the real-world utility of these tools. Future research should prioritize co-design with clinicians, real-world testing, and impact evaluation to close this gap and improve patient-centered care
Comparison of robustness, resilience and intrinsic capacity including prediction of long-term adverse health outcomes: The KORA-Age study
Get PDFBackground
Frailty, resilience and intrinsic capacity (IC) are concepts to evaluate older person`s health status, but no comparison of their associations with adverse health outcomes exists. We therefore aimed to assess which concept is most useful for determining long-term health of older adults.
Methods
Analyses were based on the KORA (Cooperative Health Research in the Region of Augsburg)-Age study (n = 940, 65–93 years). Frailty was evaluated using the physical frailty-phenotype by Fried et al. For comparability to resilience and IC, we chose the protective concept of robustness instead of frailty in the present analysis. Resilience was measured by the 11-item resilience-scale. The IC-score was based on 4 domains (locomotion, cognition, vitality and psychiatric capacities). Associations with falls, disability, and hospitalization at 3-year and 7-year follow-up and with mortality were evaluated by multivariable adjusted logistic and Cox regression. Concept overlaps were illustrated by a Venn-diagram.
Results
In the fully adjusted models, robustness showed significant inverse associations with most outcomes (3-year follow-up: OR (95%CI): disability 0.448 (0.300−0.668), 7-year follow-up: falls 0.477 (0.298−0.764), hospitalization 0.547 (0.349−0.856), and all-cause mortality 0.649 (0.460−0.915)) while resilience and IC showed significant inverse associations with disability only (e.g., 7-year-follow-up: resilience: 0.467 (0.304−0.716), IC: 0.510 (0.329−0.793)). 23% of the participants met the criteria for both robustness and IC while 22% met those for robustness and resilience.
Conclusion
Robustness was the most useful concept, showing the strongest protective associations for most adverse health outcomes. IC and resilience showed their main strengths in capturing protective associations for disabilities. Robustness overlapped with resilience and IC, supporting the concept of mind-body-interaction