Introduction
The term primary progressive aphasia (PPA) sums up the non‐fluent (nfv), the semantic (sv), and the logopenic (lv) variant. Up to now, there is only limited data available concerning ...magnetic resonance imaging volumetry to monitor disease progression.
Methods
Structural brain imaging and an extensive assessment were applied at baseline and up to 4‐year(s) follow‐up in 269 participants. With automated atlas‐based volumetry 56 brain regions were assessed. Atrophy progression served to calculate sample sizes for therapeutic trials.
Results
At baseline highest atrophy appeared in parts of the left frontal lobe for nfvPPA (–17%) and of the left temporal lobe for svPPA (–34%) and lvPPA (–24%). Severest progression within 1‐year follow‐up occurred in the basal ganglia in nfvPPA (–7%), in the hippocampus/amygdala in svPPA (–9%), and in (medial) temporal regions in lvPPA (–6%).
Conclusion
PPA presents as a left‐dominant, mostly gray matter sensitive disease with considerable atrophy at baseline that proceeds variant‐specific.
The applause sign, i.e., the inability to execute the same amount of claps as performed by the examiner, was originally reported as a sign specific for progressive supranuclear palsy (PSP). Recent ...research, however, has provided evidence for the occurrence of the applause sign in various conditions. The aim of this study was to determine the prevalence of the applause sign and correlate its presence with neuropsychological and MRI volumetry findings in frontotemporal lobar degeneration and related conditions. The applause sign was elicited with the three clap test (TCT), with a higher score indicating poorer performance. Data were recorded from 272 patients from the cohort of the German consortium for frontotemporal lobar degeneration (FTLDc): 111 with behavioral variant frontotemporal dementia (bvFTD), 98 with primary progressive aphasia (PPA), 30 with progressive supranuclear palsy Richardson’s syndrome, 17 with corticobasal syndrome (CBS) and 16 with amyotrophic lateral sclerosis with frontotemporal dementia (ALS/FTD). For comparison, 29 healthy elderly control subjects (HC) were enrolled in the study. All subjects underwent detailed language and neuropsychological assessment. In a subset of 156 subjects, atlas-based volumetry was performed. The applause sign occurred in all patient groups (40% in PSP, 29.5% in CBS, 25% in ALS/FTD, 13.3% in PPA and 9.0% in bvFTD) but not in healthy controls. The prevalence was highest in PSP patients. It was significantly more common in PSP as compared to bvFTD, PPA and HC. The comparison between the other groups failed to show a significant difference regarding the occurrence of the applause sign. The applause sign was highly correlated to a number of neuropsychological findings, especially to measures of executive, visuospatial, and language function as well as measures of disease severity. TCT scores showed an inverse correlation with the volume of the ventral diencephalon and the pallidum. Furthermore the volume of the ventral diencephalon and pallidum were significantly smaller in patients displaying the applause sign. Our study confirms the occurrence of the applause sign in bvFTD, PSP and CBS and adds PPA and ALS/FTD to these conditions. Although still suggestive of PSP, clinically it must be interpreted with caution. From the correlation with various cognitive measures we suggest the applause sign to be indicative of disease severity. Furthermore we suggest that the applause sign represents dysfunction of the pallidum and the subthalamic nucleus, structures which are known to play important roles in response inhibition.
In glioma-in contrast to various other cancers-the impact of T-lymphocytes on clinical outcome is not clear. We investigated the clinical relevance and regulation of T-cell infiltration in glioma.
...T-cell subpopulations from entire sections of 93 WHO°II-IV gliomas were computationally identified using markers CD3, CD8, and Foxp3; survival analysis was then done on primary glioblastomas (pGBM). Endothelial cells expressing cellular adhesion molecules (CAM) were similarly computationally quantified from the same glioma tissues. Influence of prominent cytokines (as measured by ELISA from 53 WHO°II-IV glioma lysates) on CAM-expression in GBM-isolated endothelial cells was determined using flow cytometry. The functional relevance of the cytokine-mediated CAM regulation was tested in a transmigration assay using GBM-derived endothelial cells and autologous T-cells.
Infiltration of all T-cell subsets increased in high-grade tumors. Most strikingly, within pGBM, elevated numbers of intratumoral effector T cells (T(eff), cytotoxic and helper) significantly correlated with a better survival; regulatory T cells were infrequently present and not associated with GBM patient outcome. Interestingly, increased infiltration of T(eff) cells was related to the expression of ICAM-1 on the vessel surface. Transmigration of autologous T cells in vitro was markedly reduced in the presence of CAM-blocking antibodies. We found that TGF-β molecules impeded transmigration and downregulated CAM-expression on GBM-isolated endothelial cells; blocking TGF-β receptor signaling increased transmigration.
This study provides comprehensive and novel insights into occurrence and regulation of T-cell infiltration in glioma. Specifically, targeting TGF-β1 and TGF-β2 might improve intratumoral T-cell infiltration and thus enhance effectiveness of immunotherapeutic approaches.
The study of very early human placentation is largely limited due to ethical restrictions on the use of embryonic tissue and the fact that the placental anatomy of common laboratory animal models ...varies considerably from that of humans. In recent years several promising models, including trophoblast stem cell-derived organoids, have been developed that have also proven useful for the study of important trophoblast differentiation processes. However, the consideration of maternal blood flow in trophoblast invasion models currently appears to be limited to animal models. An almost forgotten model to study the invasive behavior of trophoblasts is to culture them in vitro on the chicken chorioallantoic membrane (CAM), showing an extraembryonic vascular network in its mesenchymal stroma that is continuously perfused by the chicken embryonic blood circulation.
Here, we present an extension of the previously described ex ovo CAM assay and describe the use of cavity-bearing trophoblast spheroids obtained from the first trimester cell line ACH-3P. We demonstrate how spheroids penetrated the CAM and that erosion of CAM vessels by trophoblasts led to filling of the spheroid cavities with chicken blood, mimicking initial steps of intervillous space blood perfusion. Moreover, we prove that this model is useful for state-of-the-art techniques including immunofluorescence and in situ padlock probe hybridization, making it a versatile tool to study aspects of trophoblast invasion in presence of blood flow.
•Generation and characterization of ACH-3P spheroids with cavities.•Description of an ex ovo CAM invasion assay using spheroids.•Spheroid cavities were preserved during the invasion into the CAM.•Cavities of the spheroids were filled with blood cells after invasion into the CAM.
Background Diagnostic criteria for progressive supranuclear palsy (PSP) include midbrain atrophy in MRI and hypometabolism in 18 Ffluorodeoxyglucose (FDG)-positron emission tomography (PET) as ...supportive features. Due to limited data regarding their relative and sequential value, there is no recommendation for an algorithm to combine both modalities to increase diagnostic accuracy. This study evaluated the added value of sequential imaging using state-of-the-art methods to analyse the images regarding PSP features. Methods The retrospective study included 41 PSP patients, 21 with Richardson’s syndrome (PSP-RS), 20 with variant PSP phenotypes (vPSP) and 46 sex- and age-matched healthy controls. A pretrained support vector machine (SVM) for the classification of atrophy profiles from automatic MRI volumetry was used to analyse T1w-MRI (output: MRI-SVM-PSP score). Covariance pattern analysis was applied to compute the expression of a predefined PSP-related pattern in FDG-PET (output: PET-PSPRP expression score). Results The area under the receiver operating characteristic curve for the detection of PSP did not differ between MRI-SVM-PSP and PET-PSPRP expression score (p≥0.63): about 0.90, 0.95 and 0.85 for detection of all PSP, PSP-RS and vPSP. The MRI-SVM-PSP score achieved about 13% higher specificity and about 15% lower sensitivity than the PET-PSPRP expression score. Decision tree models selected the MRI-SVM-PSP score for the first branching and the PET-PSPRP expression score for a second split of the subgroup with normal MRI-SVM-PSP score, both in the whole sample and when restricted to PSP-RS or vPSP. Conclusions FDG-PET provides added value for PSP-suspected patients with normal/inconclusive T1w-MRI, regardless of PSP phenotype and the methods to analyse the images for PSP-typical features.
Pluripotent embryonic stem cells (ESCs) are characterised by their capacity to self-renew indefinitely while maintaining the potential to differentiate into all cell types of an adult organism. Both ...the undifferentiated and differentiated states are defined by specific gene expression programs that are regulated at the chromatin level. Here, we have analysed the contribution of the H3K27me2- and H3K27me23-specific demethylases KDM6A and KDM6B to murine ESC differentiation by employing the GSK-J4 inhibitor, which is specific for KDM6 proteins, and by targeted gene knockout (KO) and knockdown. We observe that inhibition of the H3K27 demethylase activity induces DNA damage along with activation of the DNA damage response (DDR) and cell death in differentiating but not in undifferentiated ESCs. Laser microirradiation experiments revealed that the H3K27me3 mark, but not the KDM6B protein, colocalise with γH2AX-positive sites of DNA damage in differentiating ESCs. Lack of H3K27me3 attenuates the GSK-J4-induced DDR in differentiating Eed-KO ESCs. Collectively, our findings indicate that differentiating ESCs depend on KDM6 and that the H3K27me3 demethylase activity is crucially involved in DDR and survival of differentiating ESCs.
Dietary recommendations in inflammatory bowel disease (IBD) are inconclusive, and patients may follow restrictive diets with increased risk of malnutrition. The aim of this study was to compare ...dietary intakes and nutritional status in men and women with newly diagnosed IBD with a general population sample, and to investigate whether intakes were in line with the Nordic Nutrition Recommendations.
This was a cross-sectional study including adults≥ 40 years with IBD from the Inflammatory Bowel Disease in South-Eastern Norway (IBSEN) III cohort study. A validated food frequency questionnaire (FFQ) was used in dietary data collection, and a sample from the seventh survey of the Tromsø Study was included as a comparison group.
A total of 227 men and women with IBD were included. IBD patients had higher intake of grain products, sweetened beverages, energy, fat and polyunsaturated fat (PUFA), but lower intake of dairy products, alcohol and iodine compared to adults from the comparison sample (
< 0.01). Intakes of saturated fat and carbohydrates in both genders, and vitamin D in women were not within recommended levels. Anemia and hypoalbuminemia were more prevalent in IBD patients than in the comparison sample.
Dietary intakes in newly diagnosed IBD patients were mostly in line with Nordic Nutrition Recommendations. Higher proportion of IBD patients exceeded recommended allowances of fat and added sugar than the comparison sample. Insufficient micronutrient intake, anemia and hypoalbuminemia are present challenges in IBD patients that require monitoring.
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