| 1. |
- Boström, Gustaf, et al.
(författare)
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Different Inflammatory Signatures in Alzheimer's Disease and Frontotemporal Dementia Cerebrospinal Fluid
- 2021
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Ingår i: Journal of Alzheimer's Disease. - : IOS Press. - 1387-2877 .- 1875-8908. ; 81:2, s. 629-640
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Tidskriftsartikel (refereegranskat)abstract
- Background: Neuroinflammatory processes are common in neurodegenerative diseases such as Alzheimer's disease (AD) and frontotemporal dementia (FTD), but current knowledge is limited as to whether cerebrospinal fluid (CSF) levels of neuroinflammatory proteins are altered in these diseases.Objective: To identify and characterize neuroinflammatory signatures in CSF from patients with AD, mild cognitive impairment (MCI), and FTD.Methods: We used proximity extension assay and ANOVA to measure and compare levels of 92 inflammatory proteins in CSF from 42 patients with AD, 29 with MCI due to AD (MCI/AD), 22 with stable MCI, 42 with FTD, and 49 control subjects, correcting for age, gender, collection unit, and multiple testing.Results: Levels of matrix metalloproteinase-10 (MMP-10) were increased in AD, MCI/AD, and FTD compared with controls (AD: fold change [FC] = 1.32, 95% confidence interval [CI] 1.14-1.53, q = 0.018; MCI/AD: FC = 1.53, 95% CI 1.20-1.94, q = 0.045; and FTD: FC = 1.42, 95% CI 1.10-1.83, q = 0.020). MMP-10 and eleven additional proteins were increased in MCI/AD, compared with MCI (q < 0.05). In FTD, 36 proteins were decreased, while none was decreased in AD or MCI/AD, compared with controls (q < 0.05).Conclusion: In this cross-sectional multi-center study, we found distinct patterns of CSF inflammatory marker levels in FTD and in both early and established AD, suggesting differing neuroinflammatory processes in the two disorders.
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| 2. |
- Bronge, Mattias, et al.
(författare)
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Identification of four novel T cell autoantigens and personal autoreactive profiles in multiple sclerosis
- 2022
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Ingår i: Science Advances. - : American Association for the Advancement of Science (AAAS). - 2375-2548. ; 8:17
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Tidskriftsartikel (refereegranskat)abstract
- Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS), in which pathological T cells, likely autoimmune, play a key role. Despite its central importance, the autoantigen repertoire remains largely uncharacterized. Using a novel in vitro antigen delivery method combined with the Human Protein Atlas library, we screened for T cell autoreactivity against 63 CNS-expressed proteins. We identified four previously unreported autoantigens in MS: fatty acid-binding protein 7, prokineticin-2, reticulon-3, and synaptosomal-associated protein 91, which were verified to induce interferon-gamma responses in MS in two cohorts. Autoreactive profiles were heterogeneous, and reactivity to several autoantigens was MS-selective. Autoreactive T cells were predominantly CD4(+) and human leukocyte antigen-DR restricted. Mouse immunization induced antigen-specific responses and CNS leukocyte infiltration. This represents one of the largest systematic efforts to date in the search for MS autoantigens, demonstrates the heterogeneity of autoreactive profiles, and highlights promising targets for future diagnostic tools and immunomodulatory therapies in MS.
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| 3. |
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| 4. |
- Brundin, Martin, et al.
(författare)
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Circulating microRNA-29-5p can add to the discrimination between dilated cardiomyopathy and ischaemic heart disease
- 2021
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Ingår i: ESC Heart Failure. - : John Wiley & Sons. - 2055-5822. ; 8:5, s. 3865-3874
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Tidskriftsartikel (refereegranskat)abstract
- Aims: Heart failure describes a large and heterogeneous spectrum of underlying cardiac diseases. MicroRNAs (miRs) are small non-coding RNAs that in recent years have been shown to play an important role in the pathogenesis of heart failure. Cardiac magnetic resonance imaging is a powerful imaging modality for the evaluation of cardiac characteristics in heart failure. In this study, we sought to compare heart failure patients with a diagnosis of either idiopathic dilated cardiomyopathy (DCM) or ischaemic heart disease (IHD), in the context of serum levels of certain miRs and also magnetic resonance imaging parameters of cardiac structure and function.Methods and results: A total of 135 subjects were studied: 53 patients with DCM (age: 59 +/- 12 years, mean +/- SD), 34 patients with IHD (66 +/- 9 years), and 48 controls (64 +/- 5 years). The participants underwent baseline medical examination, blood sampling, and a cardiac magnetic resonance imaging examination at 3 Tesla (Philips Ingenia). The serum levels of seven different miRs were analysed and assessed: 16-5p, 21-5p, 29-5p, 133a-3p, 191-5p, 320a, and 423-5p, all of which have been demonstrated to play potential roles in the pathogenesis of heart failure. The patients in the DCM and IHD groups had left ventricles that had larger end-diastolic volume (P < 0.001), larger mass ( P < 0.001), and lower ejection fraction (P < 0.001) compared with controls. Serum levels of miR-29-5p were increased in DCM compared with IHD (P < 0.005) and serum levels of miR-320a were elevated in DCM compared with healthy controls ( P < 0.05). There was no significant association between miR levels and magnetic resonance imaging parameters of left ventricular structure and function.Conclusions: Circulating miR-320a can add to the discrimination between patients with DCM and healthy controls and circulating miR-29-5p can add to the discrimination between DCM and IHD.
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| 5. |
- de la Vega, Maria Pagnon, et al.
(författare)
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The Uppsala APP deletion causes early onset autosomal dominant Alzheimer's disease by altering APP processing and increasing amyloid beta fibril formation
- 2021
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Ingår i: Science Translational Medicine. - : American Association for the Advancement of Science (AAAS). - 1946-6234 .- 1946-6242. ; 13:606
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Tidskriftsartikel (refereegranskat)abstract
- Point mutations in the amyloid precursor protein gene (APP) cause familial Alzheimer's disease (AD) by increasing generation or altering conformation of amyloid beta (A beta). Here, we describe the Uppsala APP mutation (Delta 690-695), the first reported deletion causing autosomal dominant AD. Affected individuals have an age at symptom onset in their early forties and suffer from a rapidly progressing disease course. Symptoms and biomarkers are typical of AD, with the exception of normal cerebrospinal fluid (CSF) A beta 42 and only slightly pathological amyloid-positron emission tomography signals. Mass spectrometry and Western blot analyses of patient CSF and media from experimental cell cultures indicate that the Uppsala APP mutation alters APP processing by increasing beta-secretase cleavage and affecting alpha-secretase cleavage. Furthermore, in vitro aggregation studies and analyses of patient brain tissue samples indicate that the longer form of mutated A beta, A beta Upp1-42(Delta 19-24), accelerates the formation of fibrils with unique polymorphs and their deposition into amyloid plaques in the affected brain.
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| 6. |
- Henningsson, Markus, et al.
(författare)
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Quantification of epicardial fat using 3D cine Dixon MRI
- 2020
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Ingår i: BMC Medical Imaging. - : BMC. - 1471-2342. ; 20:1
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Tidskriftsartikel (refereegranskat)abstract
- Background There is an increased interest in quantifying and characterizing epicardial fat which has been linked to various cardiovascular diseases such as coronary artery disease and atrial fibrillation. Recently, three-dimensional single-phase Dixon techniques have been used to depict the heart and to quantify the surrounding fat. The purpose of this study was to investigate the merits of a new high-resolution cine 3D Dixon technique for quantification of epicardial adipose tissue and compare it to single-phase 3D Dixon in patients with cardiovascular disease. Methods Fifteen patients referred for clinical CMR examination of known or suspected heart disease were scanned on a 1.5 T scanner using single-phase Dixon and cine Dixon. Epicardial fat was segmented by three readers and intra- and inter-observer variability was calculated per slice. Cine Dixon segmentation was performed in the same cardiac phase as single-phase Dixon. Subjective image quality assessment of water and fat images were performed by three readers using a 4-point Likert scale (1 = severe; 2 = significant; 3 = mild; 4 = no blurring of cardiac structures). Results Intra-observer variability was excellent for cine Dixon images (ICC = 0.96), and higher than single-phase Dixon (ICC = 0.92). Inter-observer variability was good for cine Dixon (ICC = 0.76) and moderate for single-phase Dixon (ICC = 0.63). The intra-observer measurement error (mean +/- standard deviation) per slice for cine was - 0.02 +/- 0.51 ml (- 0.08 +/- 0.4%), and for single-phase 0.39 +/- 0.72 ml (0.18 +/- 0.41%). Inter-observer measurement error for cine was 0.46 +/- 0.98 ml (0.11 +/- 0.46%) and for single-phase 0.42 +/- 1.53 ml (0.17 +/- 0.47%). Visual scoring of the water image yielded median of 2 (interquartile range = [Q3-Q1] 2-2) for cine and median of 3 (interquartile range = 3-2) for single-phase (P < 0.05) while no significant difference was found for the fat images, both techniques yielding a median of 3 and interquartile range of 3-2. Conclusion Cine Dixon can be used to quantify epicardial fat with lower intra- and inter-observer variability compared to standard single-phase Dixon. The time-resolved information provided by the cine acquisition appears to support the delineation of the epicardial adipose tissue depot.
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| 7. |
- Netz, Joakim, et al.
(författare)
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Business disruptions and affective reactions : A strategy-as-practice perspective on fast strategic decision making
- 2020
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Ingår i: Long range planning. - : Elsevier. - 0024-6301 .- 1873-1872. ; 53:5
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Tidskriftsartikel (refereegranskat)abstract
- This study examines management teams' work in making fast strategic decisions under extreme time pressure. Focusing on affective reactions as behavioural responses to business disruptions due to unforeseen events, we elaborate the strategy-as-practice perspective by drawing upon qualitative and quantitative datasets collected from 39 sites in a corporate setting over three consecutive phases during a four-year period. The data show two types of patterns: intensity-focused and type-focused affective reactions in management teams' use of management tools as part of mental shortcuts when making fast decisions. These patterns are contingent on whether the teams functioned in contexts that had previous experience of management of similar unforeseen events. Affective reactions in the use of tool-based mental shortcuts unveil a mechanism of practices that explains middle management teams’ strategic actions during business disruption due to unforeseen events. While research predominantly suggests that affect is “bad” for management teams in crisis-related contexts, we find that this view is misleading. Affective reactions not only hinder but also aid crucial information exchanges between middle management teams and corporate levels while making strategic decisions under extreme time pressure. Therefore, we propose a reconceptualized view of managing fast strategic decision making and discuss the implications for theory and practice.
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| 8. |
- Pagnon de la Vega, María, 1994-, et al.
(författare)
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Mutation analysis of disease causing genes in patients with early onset or familial forms of Alzheimer’s disease and frontotemporal dementia
- 2022
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Ingår i: BMC Genomics. - : Springer Nature. - 1471-2164. ; 23
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Tidskriftsartikel (refereegranskat)abstract
- Background: Most dementia disorders have a clear genetic background and a number of disease genes have beenidentified. Mutations in the tau gene (MAPT) lead to frontotemporal dementia (FTD), whereas mutations in the genesfor the amyloid-β precursor protein (APP) and the presenilins (PSEN1, PSEN2) cause early-onset, dominantly inheritedforms of Alzheimer’s disease (AD).Even if mutations causing Mendelian forms of these diseases are uncommon, elucidation of the pathogenic effects ofsuch mutations have proven important for understanding the pathogenic processes. Here, we performed a screen toidentify novel pathogenic mutations in known disease genes among patients undergoing dementia investigation.Results: Using targeted exome sequencing we have screened all coding exons in eleven known dementia genes(PSEN1, PSEN2, APP, MAPT, APOE, GRN, TARDBP, CHMP2B, TREM2, VCP and FUS) in 102 patients with AD, FTD, otherdementia diagnoses or mild cognitive impairment.We found three AD patients with two previously identified pathogenic mutations in PSEN1 (Pro264Leu and Met-146Val). In this screen, we also identified the recently reported APP mutation in two siblings with AD. This mutation,named the Uppsala mutation, consists of a six amino acid intra-amyloid β deletion.In addition, we found several potentially pathogenic mutations in PSEN2, FUS, MAPT, GRN and APOE. Finally, APOE ε4was prevalent in this patient group with an allele frequency of 54%Conclusions: Among the 102 screened patients, we found two disease causing mutations in PSEN1 and one in APP,as well as several potentially pathogenic mutations in other genes related to neurodegenerative disorders. Apart fromgiving important information to the clinical investigation, the identification of disease mutations can contribute to anincreased understanding of disease mechanisms.
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| 9. |
- Treydte, Kerstin, et al.
(författare)
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Recent human-induced atmospheric drying across Europe unprecedented in the last 400 years
- 2024
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Ingår i: NATURE GEOSCIENCE. - 1752-0894 .- 1752-0908. ; 17, s. 58-65
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Tidskriftsartikel (refereegranskat)abstract
- The vapor pressure deficit reflects the difference between how much moisture the atmosphere could and actually does hold, a factor that fundamentally affects evapotranspiration, ecosystem functioning, and vegetation carbon uptake. Its spatial variability and long-term trends under natural versus human-influenced climate are poorly known despite being essential for predicting future effects on natural ecosystems and human societies such as crop yield, wildfires, and health. Here we combine regionally distinct reconstructions of pre-industrial summer vapor pressure deficit variability from Europe's largest oxygen-isotope network of tree-ring cellulose with observational records and Earth system model simulations with and without human forcing included. We demonstrate that an intensification of atmospheric drying during the recent decades across different European target regions is unprecedented in a pre-industrial context and that it is attributed to human influence with more than 98% probability. The magnitude of this trend is largest in Western and Central Europe, the Alps and Pyrenees region, and the smallest in southern Fennoscandia. In view of the extreme drought and compound events of the recent years, further atmospheric drying poses an enhanced risk to vegetation, specifically in the densely populated areas of the European temperate lowlands. The atmosphere has dried across most regions of Europe in recent decades, a trend that can be attributed primarily to human impacts, according to tree ring records spanning 400 years and Earth system model simulations.
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