80 research outputs found

    Exploring discordant low amyloid beta and high neocortical tau positron emission tomography cases

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    Introduction: Neocortical 3R4R (3-repeat/4-repeat) tau aggregates are rarely observed in the absence of amyloid beta (AĪ²). 18F-MK6240 binds specifically to the 3R4R form of tau that is characteristic of Alzheimer\u27s disease (AD). We report four cases with negative AĪ², but positive tau positron emission tomography (PET) findings. Methods: All Australian Imaging, Biomarkers and Lifestyle study of aging (AIBL) study participants with AĪ² (18F-NAV4694) and tau (18F-MK6240) PET scans were included. Centiloid \u3c 25 defined negative AĪ² PET (AĪ²ā€“). The presence of neocortical tau was defined quantitatively and visually. Results: AĪ²ā€“ PET was observed in 276 participants. Four of these participants (one cognitively unimpaired [CU], two mild cognitive impairment [MCI], one AD) had tau tracer retention in a pattern consistent with Braak tau stages V to VI. Fluid biomarkers supported a diagnosis of AD. In silico analysis of APP, PSEN1, PSEN2, and MAPT genes did not identify relevant functional mutations. Discussion: Discordant cases were infrequent (1.4% of all AĪ²ā€“ participants). In these cases, the AĪ² PET ligand may not be detecting the AĪ² that is present

    Mechanical input restrains PPARĪ³2 expression and action to preserve mesenchymal stem cell multipotentiality

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    Exercise-generated signals are pro-osteogenic and anti-adipogenic within the marrow. In vitro studies indicate that mechanical signals directly block adipogenic differentiation through activation of Ī²-catenin and by limiting PPARĪ³2 expression. Whether mechanically generated Ī²-catenin can inhibit adipogenesis during PPARĪ³ transactivation is unknown. We evaluated the ability of mechanical signals to limit adipogenesis in marrow derived mesenchymal stem cells (mdMSC) distal to activation of PPARĪ³. First, we established that mdMSC attained an adipogenic phenotype within 2-4 days in the presence of rosiglitazone (1-25 Ī¼M) and that Ī²-catenin activation via GSK3Ī² inhibition interfered with this process. Similarly, mechanical strain (3600 cycles, 2% strain daily) inhibited adipogenesis at 3 days, preventing rosiglitazone-induced PPARĪ³ upregulation as well as aP2 and adiponectin protein expression. To assess whether a reduction in PPARĪ³ expression was necessary for anti-adipogenic action, PPARĪ³2 was overexpressed: both mechanical strain and GSK3Ī² inhibition prevented expression of aP2 and adiponectin proteins despite abundant PPARĪ³2 and its ligand. To understand the fate of single cells experiencing mechanical strain we generated mdMSC from aP2-GFP reporter expressing mice. Rosiglitazone treatment for 3 days induced GFP expression in more than 80% of cells. Sorting by GFP expression revealed that the highest 20% of aP2-GFP expressing cells was responsible for the majority of adipogenic protein expression. This highly expressing GFP fraction had a reduced ability to respond to an osteogenic stimulus: BMP-2 treatment increased osterix by 12-fold in contrast to the 42-fold increase in osterix expression that resulted from BMP-2 treatment of the bottom 75% of GFP expressing cells. This suggested that highly expressing aP2-GFP cells represented more terminally differentiated adipocytes, with reduced multipotentiality. Application of mechanical strain to aP2-GFP mdMSC treated with rosiglitazone caused a two-fold decrease in the size of the upper cell fraction, suggesting that mechanical strain preserved MSC in a multipotent state. Our data show that mechanical strain restricts adipogenesis both by limiting PPARĪ³2 expression and by preventing PPARĪ³ action, protecting the potential of MSC to enter other lineages

    Personality traits and night eating syndrome in women with bulimia nervosa and binge eating disorder

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    Purpose: Previous research suggests that eating disorders may be associated with certain personality profiles; however, there is limited research investigating associations with night eating syndrome (NES). This research suggests harm avoidance personality trait is higher in NES individuals than in the general population, however, evidence of associations with other personality traits is inconsistent. To understand which personality traits are associated with NES symptoms, the current study aimed to improve understanding of the relationship between NES symptoms and a range of personality traits, addressing limitations in the earlier literature in this area by controlling for common confounders. Methods: Baseline data were analysed from an outpatient psychotherapy trial for 111 women with bulimia nervosa or binge eating disorder. Pre-treatment measures of personality traits (measured with the Temperament and character inventoryā€”revised) and NES symptoms (measured with the Night eating questionnaire) were used. Regression analyses tested associations between these variables, adjusting for potential confounders, including age and ethnicity. Results: Low cooperativeness scores were associated with greater NES symptoms in the multivariable model (mean difference: āˆ’0.10, 95% confidence intervals: āˆ’0.20 to āˆ’0.01, p = 0.033). There was weak evidence of associations between both high harm avoidance and low self-directedness personality traits and greater NES symptoms. Conclusions: This study adds to the limited research measuring associations between a range of personality traits and NES, addressing limitations of previous research. Weak evidence for an association between high harm avoidance and low self-directedness and increased NES symptoms was found. A novel association was found between low cooperativeness and greater NES symptoms. Further research is needed to validate its presence in those with and without comorbid eating disorders and to examine the relative change in NES, eating disorder symptoms and personality scores in treatments focusing on cooperativeness. Level of evidence: Level IV (cross-sectional data from a randomised controlled trial, CTB/04/08/139)

    Visually identified Tau 18F-MK6240 PET patterns in symptomatic Alzheimer\u27s disease

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    Background: In Alzheimer\u27s disease, heterogeneity has been observed in the postmortem distribution of tau neurofibrillary tangles. Visualizing the topography of tau in vivo may facilitate clinical trials and clinical practice. Objective: This study aimed to investigate whether tau distribution patterns that are limited to mesial temporal lobe (MTL)/limbic regions, and those that spare MTL regions, can be visually identified using 18F-MK6240, and whether these patterns are associated with different demographic and cognitive profiles. Methods : Tau 18F-MK6240 PET images of 151 amyloid-Ī² positive participants with mild cognitive impairment (MCI) and dementia were visually rated as: tau negative, limbic predominant (LP), MTL-sparing, and Typical by two readers. Groups were evaluated for differences in age, APOE ɛ4 carriage, hippocampal volumes, and cognition (MMSE, composite memory and non-memory scores). Voxel-wise contrasts were also performed. Results: Visual rating resulted in 59.6 % classified as Typical, 17.9 % as MTL-sparing, 9.9 % LP, and 12.6% as tau negative. Intra-rater and inter-rater reliability was strong (Cohen\u27s kappa values of 0.89 and 0.86 respectively). Tracer retention in a hook -like distribution on sagittal sequences was observed in the LP and Typical groups. The visually classified MTL-sparing group had lower APOE ɛ4 carriage and relatively preserved hippocampal volumes. Higher MTL tau was associated with greater amnestic cognitive impairment. High crtical tau was associated with greater impairments on non-memory domains of cognition, and individuals with high cortical tau were more likely to have dementia than MCI. Conclusion: Tau distribution patterns can be visually identified using 18F-MK6240 PET and are associated with differences in APOE ɛ4 carriage, hippocampal volumes, and cognition

    Impact of radiographer immediate reporting of X-rays of the chest from general practice on the lung cancer pathway (radioX): a randomised controlled trial

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    The National Optimal Lung Cancer Pathway recommends rapid progression from abnormal chest X-rays (CXRs) to CT. The impact of the more rapid reporting on the whole pathway is unknown. The aim of this study was to determine the impact of immediate reporting of CXRs requested by primary care by radiographers on the time to diagnosis of lung cancer. METHOD: People referred for CXR from primary care to a single acute district general hospital in London attended sessions that were prerandomised to either immediate radiographer (IR) reporting or standard radiographer (SR) reporting within 24 hours. CXRs were subsequently reported by radiologists blind to the radiographer reports to test the reliability of the radiographer report. Radiographer and local radiologist discordant cases were reviewed by thoracic radiologists, blinded to reporter. RESULTS: 8682 CXRs were performed between 21 June 2017 and 4 August 2018, 4096 (47.2%) for IR and 4586 (52.8%) for SR. Lung cancer was diagnosed in 49, with 27 (55.1%) for IR. The median time from CXR to diagnosis of lung cancer for IR was 32 days (IQR 19, 70) compared with 63 days (IQR 29, 78) for SR (p=0.03).8258 CXRs (95.1%) were reported by both radiographers and local radiologists. In the 1361 (16.5%) with discordance, the reviewing thoracic radiologists were equally likely to agree with local radiologist and radiographer reports. CONCLUSIONS: Immediate reporting of CXRs from primary care reduces time to diagnosis of lung cancer by half, likely due to rapid progress to CT. Radiographer reports are comparable to local radiologist reports for accuracy. TRIAL REGISTRATION: International Standard Randomised Controlled Trial Number ISRCTN21818068. Registered on 20 June 2017

    Plasma glial fibrillary acidic protein is associated with 18F-SMBT-1 PET: Two putative astrocyte reactivity biomarkers for Alzheimer\u27s disease

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    Background: Astrocyte reactivity is an early event along the Alzheimer\u27s disease (AD) continuum. Plasma glial fibrillary acidic protein (GFAP), posited to reflect astrocyte reactivity, is elevated across the AD continuum from preclinical to dementia stages. Monoamine oxidase-B (MAO-B) is also elevated in reactive astrocytes observed using 18F-SMBT-1 PET in AD. Objective: The objective of this study was to evaluate the association between the abovementioned astrocyte reactivity biomarkers. Methods: Plasma GFAP and AĪ² were measured using the SimoaĀ® platform in participants who underwent brain 18F-SMBT-1 and AĪ²-PET imaging, comprising 54 healthy control (13 AĪ²-PET+ and 41 AĪ²-PET-), 11 mild cognitively impaired (3 AĪ²-PET+ and 8 AĪ²-PET-) and 6 probable AD (5 AĪ²-PET+ and 1 AĪ²-PET-) individuals. Linear regressions were used to assess associations of interest. Results: Plasma GFAP was associated with 18F-SMBT-1 signal in brain regions prone to early AĪ² deposition in AD, such as the supramarginal gyrus (SG), posterior cingulate (PC), lateral temporal (LT) and lateral occipital cortex (LO). After adjusting for age, sex, APOE ɛ4 genotype, and soluble AĪ² (plasma AĪ²42/40 ratio), plasma GFAP was associated with 18F-SMBT-1 signal in the SG, PC, LT, LO, and superior parietal cortex (SP). On adjusting for age, sex, APOE ɛ4 genotype and insoluble AĪ² (AĪ²-PET), plasma GFAP was associated with 18F-SMBT-1 signal in the SG. Conclusion: There is an association between plasma GFAP and regional 18F-SMBT-1 PET, and this association appears to be dependent on brain AĪ² load
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