Histopathological changes and antioxidant responses in common carp (Cyprinus carpio) exposed to copper nanoparticles

This is the author accepted manuscript. The final version is available from Taylor & Francis via the DOI in this recordDespite the rapid increase of nanotechnology in a wide array of industrial sectors, the biosafety profile of nanomaterials remains undefined. The accelerated use of nanomaterials has increased the potential discharge of nanomaterials into the environment in different ways. The aquatic environment is mainly susceptible as it is likely to act as an ultimate sink for all contaminants. Therefore, this study assessed the toxicological impacts of waterborne engineered copper nanoparticles (Cu-NPs) on histology, lipid peroxidation (LPO), catalase (CAT), and glutathione (GSH) levels in the gills of common carp (Cyprinus carpio). Nanoparticles were characterized by XRD and SEM techniques. Before starting the sub-acute toxicity testing, 96 h LC50 of Cu-NPs for C. carpio was calculated as 4.44 mg/l. Then based on LC50, C. carpio of 40–45 g in weight were exposed to three sub-lethal doses of waterborne engineered Cu-NPs (0 or 0.5 or 1 or 1.5 mg/l) for a period of 14 days. The waterborne Cu-NPs have appeared to induce alterations in gill histology and oxidative stress parameters in a dose-dependent manner. The gill tissues showed degenerative secondary lamellae, necrotic lamella, fused lamella, necrosis of the primary and secondary lamella, edema, complete degeneration, epithelial lifting, degenerative epithelium, and hyperplasia in a dose-dependent manner. In the gill tissues, waterborne Cu-NPs caused a decreased level of CAT and elevated levels of LPO, and GSH in the fish exposed to the highest dose of 1.5 mg Cu-NPs/l of water. Our results indicate that the exposure to waterborne Cu-NPs was toxic to the aquatic organisms as shown by the oxidative stresses and histological alterations in C. carpio, a freshwater fish of good economic value

Cerebral rituximab uptake in multiple sclerosis: A (89)Zr-immunoPET pilot study

Previous studies have demonstrated that the chimeric monoclonal antibody rituximab significantly reduces clinical and radiological disease activity in relapsing-remitting multiple sclerosis as early as 4 weeks after the first administration. The exact mechanisms leading to this rapid effect have not yet been clarified. The aim of this positron emission tomography study was to assess central nervous system penetration as a possible explanation, using zirconium-89-labelled rituximab. No evidence was found for cerebral penetration of [(89)Zr]rituximab

Ceramic-reinforced HEA matrix composites exhibiting an excellent combination of mechanical properties

CoCrFeNi is a well-studied face centered cubic (fcc) high entropy alloy (HEA) that exhibits excellent ductility but only limited strength. The present study focusses on improving the strength-ductility balance of this HEA by addition of varying amounts of SiC using an arc melting route. Chromium present in the base HEA is found to result in decomposition of SiC during melting. Consequently, interaction of free carbon with chromium results in the in-situ formation of chromium carbide, while free silicon remains in solution in the base HEA and/or interacts with the constituent elements of the base HEA to form silicides. The changes in microstructural phases with increasing amount of SiC are found to follow the sequence: fcc → fcc + eutectic → fcc + chromium carbide platelets → fcc + chromium carbide platelets + silicides → fcc + chromium carbide platelets + silicides + graphite globules/flakes. In comparison to both conventional and high entropy alloys, the resulting composites were found to exhibit a very wide range of mechanical properties (yield strength from 277 MPa with more than 60% elongation to 2522 MPa with 6% elongation). Some of the developed high entropy composites showed an outstanding combination of mechanical properties (yield strength 1200 MPa with 37% elongation) and occupied previously unattainable regions in a yield strength versus elongation map. In addition to their significant elongation, the hardness and yield strength of the HEA composites are found to lie in the same range as those of bulk metallic glasses. It is therefore believed that development of high entropy composites can help in obtaining outstanding combinations of mechanical properties for advanced structural applications.Financial support from the Higher Education Commission of Pakistan (HEC NRPU 6019) is acknowledged. FEDER National funds FCT under the project CEMMPRE, ref. “UIDB/00285/2020” is also acknowledged.info:eu-repo/semantics/publishedVersio

Sex-differences in the association of social health and marital status with blood-based immune and neurodegeneration markers in a cohort of community-dwelling older adults

Background: The immune system has been proposed to play a role in the link between social health and all-cause dementia risk. We explored cross-sectional and longitudinal associations between social health, immune system balance and plasma neurodegeneration markers in community-dwelling older adults, and explored whether the balance between innate and adaptive immunity mediates associations between social health and both cognition and total brain volume. Methods: Social health markers (social support, marital status, loneliness) were measured in the Rotterdam Study between 2002–2008. Immune system cell counts and balance were assessed repeatedly from 2002 to 2016 using white blood-cell-based indices and individual counts (granulocyte-to-lymphocyte ratio (GLR), platelet-to-lymphocyte ratio (PLR), and systemic immune-inflammation index (SII)). Plasma neurodegeneration biomarkers (amyloid-β40, amyloid-β42, total tau and neurofilament light chain) were measured once from blood samples collected between 2002–2008. Global cognitive function and total brain volume (MRI) were measured at the follow-up visit between 2009–2014. We used linear mixed models to study longitudinal associations and performed causal mediation analyses. Results: In 8374 adults (mean age 65.7, 57 % female), never married participants (n = 394) had higher GLR, PLR and SII compared to married peers at baseline and during follow-up, indicating imbalance towards innate immunity. Being never married was associated with higher plasma amyloid-β40, and being widowed or divorced with higher plasma total tau levels at baseline. Widowed or divorced males, but not females, had higher GLR, PLR and SII at baseline. Higher social support was associated with lower PLR in females, but higher PLR in males. Loneliness was not associated with any of the immune system balance ratios. Never married males had higher levels of all plasma neurodegeneration markers at baseline. Immune system balance did not mediate associations between social health and cognition or total brain volume, but does interact with marital status. Conclusion: This study indicates that marital status is associated with blood-based immune system markers toward innate immunity and higher levels of plasma neurodegeneration markers. This is particularly evident for never married or previously married male older adults compared to married or female peers.</p

Sex-differences in the association of social health and marital status with blood-based immune and neurodegeneration markers in a cohort of community-dwelling older adults

Background: The immune system has been proposed to play a role in the link between social health and all-cause dementia risk. We explored cross-sectional and longitudinal associations between social health, immune system balance and plasma neurodegeneration markers in community-dwelling older adults, and explored whether the balance between innate and adaptive immunity mediates associations between social health and both cognition and total brain volume. Methods: Social health markers (social support, marital status, loneliness) were measured in the Rotterdam Study between 2002–2008. Immune system cell counts and balance were assessed repeatedly from 2002 to 2016 using white blood-cell-based indices and individual counts (granulocyte-to-lymphocyte ratio (GLR), platelet-to-lymphocyte ratio (PLR), and systemic immune-inflammation index (SII)). Plasma neurodegeneration biomarkers (amyloid-β40, amyloid-β42, total tau and neurofilament light chain) were measured once from blood samples collected between 2002–2008. Global cognitive function and total brain volume (MRI) were measured at the follow-up visit between 2009–2014. We used linear mixed models to study longitudinal associations and performed causal mediation analyses. Results: In 8374 adults (mean age 65.7, 57 % female), never married participants (n = 394) had higher GLR, PLR and SII compared to married peers at baseline and during follow-up, indicating imbalance towards innate immunity. Being never married was associated with higher plasma amyloid-β40, and being widowed or divorced with higher plasma total tau levels at baseline. Widowed or divorced males, but not females, had higher GLR, PLR and SII at baseline. Higher social support was associated with lower PLR in females, but higher PLR in males. Loneliness was not associated with any of the immune system balance ratios. Never married males had higher levels of all plasma neurodegeneration markers at baseline. Immune system balance did not mediate associations between social health and cognition or total brain volume, but does interact with marital status. Conclusion: This study indicates that marital status is associated with blood-based immune system markers toward innate immunity and higher levels of plasma neurodegeneration markers. This is particularly evident for never married or previously married male older adults compared to married or female peers.</p

Harmonization of brain PET images in multi-center PET studies using Hoffman phantom scan

Background: Image harmonization has been proposed to minimize heterogeneity in brain PET scans acquired in multi-center studies. However, standard validated methods and software tools are lacking. Here, we assessed the performance of a framework for the harmonization of brain PET scans in a multi-center European clinical trial. / Method: Hoffman 3D brain phantoms were acquired in 28 PET systems and reconstructed using site-specific settings. Full Width at Half Maximum (FWHM) of the Effective Image Resolution (EIR) and harmonization kernels were estimated for each scan. The target EIR was selected as the coarsest EIR in the imaging network. Using “Hoffman 3D brain Analysis tool,” indicators of image quality were calculated before and after the harmonization: The Coefficient of Variance (COV%), Gray Matter Recovery Coefficient (GMRC), Contrast, Cold-Spot RC, and left-to-right GMRC ratio. A COV% ≤ 15% and Contrast ≥ 2.2 were set as acceptance criteria. The procedure was repeated to achieve a 6-mm target EIR in a subset of scans. The method’s robustness against typical dose-calibrator-based errors was assessed. / Results: The EIR across systems ranged from 3.3 to 8.1 mm, and an EIR of 8 mm was selected as the target resolution. After harmonization, all scans met acceptable image quality criteria, while only 13 (39.4%) did before. The harmonization procedure resulted in lower inter-system variability indicators: Mean ± SD COV% (from 16.97 ± 6.03 to 7.86 ± 1.47%), GMRC Inter-Quartile Range (0.040–0.012), and Contrast SD (0.14–0.05). Similar results were obtained with a 6-mm FWHM target EIR. Errors of ± 10% in the DRO activity resulted in differences below 1 mm in the estimated EIR. / Conclusion: Harmonizing the EIR of brain PET scans significantly reduced image quality variability while minimally affecting quantitative accuracy. This method can be used prospectively for harmonizing scans to target sharper resolutions and is robust against dose-calibrator errors. Comparable image quality is attainable in brain PET multi-center studies while maintaining quantitative accuracy

Amyloid-β, cortical thickness, and subsequent cognitive decline in cognitively normal oldest-old.

OBJECTIVE: To investigate the relationship between amyloid-β (Aβ) deposition and markers of brain structure on cognitive decline in oldest-old individuals with initial normal cognition. METHODS: We studied cognitive functioning in four domains at baseline and change over time in fifty-seven cognitively intact individuals from the EMIF-AD 90+ study. Predictors were Aβ status determined by [18 F]-flutemetamol PET (normal = Aβ - vs. abnormal = Aβ+), cortical thickness in 34 regions and hippocampal volume. Mediation analyses were performed to test whether effects of Aβ on cognitive decline were mediated by atrophy of specific anatomical brain areas. RESULTS: Subjects had a mean age of 92.7 ± 2.9 years, of whom 19 (33%) were Aβ+. Compared to Aβ-, Aβ+ individuals showed steeper decline on memory (β ± SE = -0.26 ± 0.09), and processing speed (β ± SE = -0.18 ± 0.08) performance over 1.5 years (P < 0.05). Furthermore, medial and lateral temporal lobe atrophy was associated with steeper decline in memory and language across individuals. Mediation analyses revealed that part of the memory decline observed in Aβ+ individuals was mediated through parahippocampal atrophy. INTERPRETATION: These results show that Aβ abnormality even in the oldest old with initially normal cognition is not part of normal aging, but is associated with a decline in cognitive functioning. Other pathologies may also contribute to decline in the oldest old as cortical thickness predicted cognitive decline similarly in individuals with and without Aβ pathology

Exploring effects of Souvenaid on cerebral glucose metabolism in Alzheimer's disease

Introduction Alzheimer's disease (AD) is associated with synapse loss. Souvenaid, containing the specific nutrient combination Fortasyn Connect, was designed to improve synapse formation and function. The NL-ENIGMA study explored the effect of Souvenaid on synapse function in early AD by assessing cerebral glucose metabolism (CMRglc) with 18F-fluorodeoxyglucose ([18F]FDG) positron emission tomography (PET). Methods We conducted an exploratory double-blind randomized controlled single-center trial. Fifty patients with mild cognitive impairment or mild dementia with evidence of amyloid pathology (cerebrospinal fluid or PET) were stratified for MMSE (20–24 and 25–30) and randomly 1:1 allocated to 24-week daily administration of 125 mL Souvenaid (n = 25) or placebo (n = 25). Dynamic 60-minute [18F]FDG-PET scans (21 frames) with arterial sampling were acquired at baseline and 24 weeks. CMRglc was estimated by quantitative (Ki) and semiquantitative (standardized uptake value ratio, reference cerebellar gray matter) measurements in five predefined regions of interest and a composite region of interest. Change from baseline in CMRglc was compared between treatment groups by analysis of variance, adjusted for baseline CMRglc and MMSE stratum. Additional exploratory outcome parameters included voxel-based analyses by Statistical Parametric Mapping. Results No baseline differences between treatment groups were found (placebo/intervention: n = 25/25; age 66 ± 8/65 ± 7 years; female 44%/48%; MMSE 25 ± 3/25 ± 3). [18F]FDG-PET data were available for quantitative (placebo n = 19, intervention n = 18) and semiquantitative (placebo n = 20, intervention n = 22) analyses. At follow-up, no change within treatment groups and no statistically significant difference in change between treatment groups in CMRglc in any regions of interest were found by both quantitative and semiquantitative analyses. No treatment effect was found in the cerebellar gray matter using quantitative measures. The additional Statistical Parametric Mapping analyses did not yield consistent differences between treatment groups. Discussion In this exploratory trial, we found no robust effect of 24-week intervention with Souvenaid on synapse function measured by [18F]FDG-PET. Possible explanations include short duration of treatment

Assessment of the appropriate use criteria for amyloid PET in an unselected memory clinic cohort: The ABIDE project

Introduction The objective of this study was to assess the usefulness of the appropriate use criteria (AUC) for amyloid imaging in an unselected cohort. Methods We calculated sensitivity and specificity of appropriate use (increased confidence and management change), as defined by Amyloid Imaging Taskforce in the AUC, and other clinical utility outcomes. Furthermore, we compared differences in post–positron emission tomography diagnosis and management change between “AUC-consistent” and “AUC-inconsistent” patients. Results Almost half (250/507) of patients were AUC-consistent. In both AUC-consistent and AUC-inconsistent patients, post–positron emission tomography diagnosis (28%–21%) and management (32%–17%) change was substantial. The Amyloid Imaging Taskforce's definition of appropriate use occurred in 55/507 (13%) patients, detected by the AUC with a sensitivity of 93%, and a specificity of 56%. Diagnostic changes occurred independently of AUC status (sensitivity: 57%, specificity: 53%). Discussion The current AUC are not sufficiently able to discriminate between patients who will benefit from amyloid positron emission tomography and those who will not

Strategies to reduce sample sizes in Alzheimer’s disease primary and secondary prevention trials using longitudinal amyloid PET imaging

BACKGROUND: Detecting subtle-to-moderate biomarker changes such as those in amyloid PET imaging becomes increasingly relevant in the context of primary and secondary prevention of Alzheimer's disease (AD). This work aimed to determine if and when distribution volume ratio (DVR; derived from dynamic imaging) and regional quantitative values could improve statistical power in AD prevention trials. METHODS: Baseline and annualized % change in [11C]PIB SUVR and DVR were computed for a global (cortical) and regional (early) composite from scans of 237 cognitively unimpaired subjects from the OASIS-3 database ( www.oasis-brains.org ). Bland-Altman and correlation analyses were used to assess the relationship between SUVR and DVR. General linear models and linear mixed effects models were used to determine effects of age, sex, and APOE-ε4 carriership on baseline and longitudinal amyloid burden. Finally, differences in statistical power of SUVR and DVR (cortical or early composite) were assessed considering three anti-amyloid trial scenarios: secondary prevention trials including subjects with (1) intermediate-to-high (Centiloid > 20.1), or (2) intermediate (20.1 < Centiloid ≤ 49.4) amyloid burden, and (3) a primary prevention trial focusing on subjects with low amyloid burden (Centiloid ≤ 20.1). Trial scenarios were set to detect 20% reduction in accumulation rates across the whole population and in APOE-ε4 carriers only. RESULTS: Although highly correlated to DVR (ρ = .96), cortical SUVR overestimated DVR cross-sectionally and in annual % change. In secondary prevention trials, DVR required 143 subjects per arm, compared with 176 for SUVR. Both restricting inclusion to individuals with intermediate amyloid burden levels or to APOE-ε4 carriers alone further reduced sample sizes. For primary prevention, SUVR required less subjects per arm (n = 855) compared with DVR (n = 1508) and the early composite also provided considerable sample size reductions (n = 855 to n = 509 for SUVR, n = 1508 to n = 734 for DVR). CONCLUSION: Sample sizes in AD secondary prevention trials can be reduced by the acquisition of dynamic PET scans and/or by restricting inclusion to subjects with intermediate amyloid burden or to APOE-ε4 carriers only. Using a targeted early composite only leads to reductions of sample size requirements in primary prevention trials. These findings support strategies to enable smaller Proof-of-Concept Phase II clinical trials to better streamline drug development