Search

© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/ by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com, Several CSF and blood biomarkers for genetic frontotemporal dementia have been proposed, including those reflecting neuroaxonal loss (neurofilament light chain and phosphorylated neurofilament heavy chain), synapse dysfunction [neuronal pentraxin 2 (NPTX2)], astrogliosis (glial fibrillary acidic protein) and complement activation (C1q, C3b). Determining the sequence in which biomarkers become abnormal over the course of disease could facilitate disease staging and help identify mutation carriers with prodromal or early-stage frontotemporal dementia, which is especially important as pharmaceutical trials emerge. We aimed to model the sequence of biomarker abnormalities in presymptomatic and symptomatic genetic frontotemporal dementia using cross-sectional data from the Genetic Frontotemporal dementia Initiative (GENFI), a longitudinal cohort study. Two-hundred and seventy-five presymptomatic and 127 symptomatic carriers of mutations in GRN, C9orf72 or MAPT, as well as 247 non-carriers, were selected from the GENFI cohort based on availability of one or more of the aforementioned biomarkers. Nine presymptomatic carriers developed symptoms within 18 months of sample collection ('converters'). Sequences of biomarker abnormalities were modelled for the entire group using discriminative event-based modelling (DEBM) and for each genetic subgroup using co-initialized DEBM. These models estimate probabilistic biomarker abnormalities in a data-driven way and do not rely on previous diagnostic information or biomarker cut-off points. Using cross-validation, subjects were subsequently assigned a disease stage based on their position along the disease progression timeline. CSF NPTX2 was the first biomarker to become abnormal, followed by blood and CSF neurofilament light chain, blood phosphorylated neurofilament heavy chain, blood glial fibrillary acidic protein and finally CSF C3b and C1q. Biomarker orderings did not differ significantly between genetic subgroups, but more uncertainty was noted in the C9orf72 and MAPT groups than for GRN. Estimated disease stages could distinguish symptomatic from presymptomatic carriers and non-carriers with areas under the curve of 0.84 (95% confidence interval 0.80-0.89) and 0.90 (0.86-0.94) respectively. The areas under the curve to distinguish converters from non-converting presymptomatic carriers was 0.85 (0.75-0.95). Our data-driven model of genetic frontotemporal dementia revealed that NPTX2 and neurofilament light chain are the earliest to change among the selected biomarkers. Further research should investigate their utility as candidate selection tools for pharmaceutical trials. The model's ability to accurately estimate individual disease stages could improve patient stratification and track the efficacy of therapeutic interventions., This study was supported in the Netherlands by two Memorabel grants from Deltaplan Dementie (The Netherlands Organisation for Health Research and Development and Alzheimer Nederland; grant numbers 733050813,733050103 and 733050513), the Bluefield Project to Cure Frontotemporal Dementia, the Dioraphte foundation (grant number 1402 1300), the European Joint Programme—Neurodegenerative Disease Research and the Netherlands Organisation for Health Research and Development (PreFrontALS: 733051042, RiMod-FTD: 733051024); V.V. and S.K. have received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement no. 666992 (EuroPOND). E.B. was supported by the Hartstichting (PPP Allowance, 2018B011); in Belgium by the Mady Browaeys Fonds voor Onderzoek naar Frontotemporale Degeneratie; in the UK by the MRC UK GENFI grant (MR/M023664/1); J.D.R. is supported by an MRC Clinician Scientist Fellowship (MR/M008525/1) and has received funding from the NIHR Rare Disease Translational Research Collaboration (BRC149/NS/MH); I.J.S. is supported by the Alzheimer’s Association; J.B.R. is supported by the Wellcome Trust (103838); in Spain by the Fundació Marató de TV3 (20143810 to R.S.V.); in Germany by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany’s Excellence Strategy within the framework of the Munich Cluster for Systems Neurology (EXC 2145 SyNergy—ID 390857198) and by grant 779357 ‘Solve-RD’ from the Horizon 2020 Research and Innovation Programme (to MS); in Sweden by grants from the Swedish FTD Initiative funded by the Schörling Foundation, grants from JPND PreFrontALS Swedish Research Council (VR) 529–2014-7504, Swedish Research Council (VR) 2015–02926, Swedish Research Council (VR) 2018–02754, Swedish Brain Foundation, Swedish Alzheimer Foundation, Stockholm County Council ALF, Swedish Demensfonden, Stohnes foundation, Gamla Tjänarinnor, Karolinska Institutet Doctoral Funding and StratNeuro. H.Z. is a Wallenberg Scholar.

Availability of data and materials: The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request. Supplementary Information: Additional file 1 of A panel of CSF proteins separates genetic frontotemporal dementia from presymptomatic mutation carriers: a GENFI study; Additional file 2 of A panel of CSF proteins separates genetic frontotemporal dementia from presymptomatic mutation carriers: a GENFI study; both files are available online at https://doi.org/10.1186/s13024-021-00499-4 Copyright © The Author(s) 2021. Background: A detailed understanding of the pathological processes involved in genetic frontotemporal dementia is critical in order to provide the patients with an optimal future treatment. Protein levels in CSF have the potential to reflect different pathophysiological processes in the brain. We aimed to identify and evaluate panels of CSF proteins with potential to separate symptomatic individuals from individuals without clinical symptoms (unaffected), as well as presymptomatic individuals from mutation non-carriers. Methods: A multiplexed antibody-based suspension bead array was used to analyse levels of 111 proteins in CSF samples from 221 individuals from families with genetic frontotemporal dementia. The data was explored using LASSO and Random forest. Results: When comparing affected individuals with unaffected individuals, 14 proteins were identified as potentially important for the separation. Among these, four were identified as most important, namely neurofilament medium polypeptide (NEFM), neuronal pentraxin 2 (NPTX2), neurosecretory protein VGF (VGF) and aquaporin 4 (AQP4). The combined profile of these four proteins successfully separated the two groups, with higher levels of NEFM and AQP4 and lower levels of NPTX2 in affected compared to unaffected individuals. VGF contributed to the models, but the levels were not significantly lower in affected individuals. Next, when comparing presymptomatic GRN and C9orf72 mutation carriers in proximity to symptom onset with mutation non-carriers, six proteins were identified with a potential to contribute to a separation, including progranulin (GRN). Conclusion: In conclusion, we have identified several proteins with the combined potential to separate affected individuals from unaffected individuals, as well as proteins with potential to contribute to the separation between presymptomatic individuals and mutation non-carriers. Further studies are needed to continue the investigation of these proteins and their potential association to the pathophysiological mechanisms in genetic FTD. This study has received support from the Swedish FTD initiative funded by the Schörling Family Foundation. This work was also funded by KTH Center for Applied Precision Medicine (KCAP) funded by the Erling-Persson Family Foundation, grants from Vetenskapsrådet Dnr 529-2014-7504, VR 2015-02926 and 2018-02754, Swedish Alzheimer Foundation, Swedish Brain Foundation, Åhlén foundation, Demensfonden, Stohnes foundation, Gamla Tjänarinnor and Stockholm County Council ALF. Furthermore, support was received by the MRC UK GENFI grant (MR/M023664/1), the Bluefield Project, the JPND GENFI-PROX grant (2019-02248), the Dioraphte Foundation [grant numbers 09-02-00]; the Association for Frontotemporal Dementias Research Grant 2009; The Netherlands Organization for Scientific Research (NWO) (grant HCMI 056-13-018); ZonMw Memorabel (Deltaplan Dementie), (project numbers 733 050 103 and 733 050 813); JPND PreFrontAls consortium (project number 733051042). JDR is supported by an MRC Clinician Scientist Fellowship (MR/M008525/1) and has received funding from the NIHR Rare Disease Translational Research Collaboration (BRC149/NS/MH). Several authors of this publication are members of the European Reference Network for Rare Neurological Diseases - Project ID No 739510. M.S. was supported by the JPND grant “GENFI-prox” (by DLR/BMBF to M. S, joint with JDR., J.vS., M.O., B.B. and C.G.). Open Access funding provided by Royal Institute of Technology.

© 2020 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)., A key symptom of frontotemporal dementia (FTD) is difficulty interacting socially with others. Social cognition problems in FTD include impaired emotion processing and theory of mind difficulties, and whilst these have been studied extensively in sporadic FTD, few studies have investigated them in familial FTD. Facial Emotion Recognition (FER) and Faux Pas (FP) recognition tests were used to study social cognition within the Genetic Frontotemporal Dementia Initiative (GENFI), a large familial FTD cohort of C9orf72, GRN, and MAPT mutation carriers. 627 participants undertook at least one of the tasks, and were separated into mutation-negative healthy controls, presymptomatic mutation carriers (split into early and late groups) and symptomatic mutation carriers. Groups were compared using a linear regression model with bootstrapping, adjusting for age, sex, education, and for the FP recognition test, language. Neural correlates of social cognition deficits were explored using a voxel-based morphometry (VBM) study. All three of the symptomatic genetic groups were impaired on both tasks with no significant difference between them. However, prior to onset, only the late presymptomatic C9orf72 mutation carriers on the FER test were impaired compared to the control group, with a subanalysis showing differences particularly in fear and sadness. The VBM analysis revealed that impaired social cognition was mainly associated with a left hemisphere predominant network of regions involving particularly the striatum, orbitofrontal cortex and insula, and to a lesser extent the inferomedial temporal lobe and other areas of the frontal lobe. In conclusion, theory of mind and emotion processing abilities are impaired in familial FTD, with early changes occurring prior to symptom onset in C9orf72 presymptomatic mutation carriers. Future work should investigate how performance changes over time, in order to gain a clearer insight into social cognitive impairment over the course of the disease.

Background and aims Increasing evidence suggests that inflammation plays an important role in brain aging and neurodegeneration. Pathological studies demonstrate the presence of C-reactive protein (CRP) in the senile plaques and neurofibrillary tangles in Alzheimer's disease (AD) brain tissue suggesting that CRP may play a role in its neuropathological processes. Some findings suggest that midlife elevations of serum CRP are a risk factor for AD. However, others found lower CRP levels in mild or moderate AD than in controls, suggesting that CRP levels could be different in different stages of disease. We aimed to assess the role of CRP as a predictor of Mild cognitive impairment (MCI) conversion into AD dementia. Methods We retrospectively reviewed the cohort of MCI patients followed at the Dementia Clinic, Neurology Department of University Hospital of Coimbra. We collected demographical, neuropsychological, genetic and laboratorial variables (including serum CRP measurements at the time of baseline laboratory tests). A Cox regression model was performed adjusted for the collected variables preconsidered to be predictors of dementia and the variable being studied (CRP) to assess for independent predictors of conversion. Results We included 130 patients, 58.5% female, with a mean age of onset of 65.5 ± 9.1 years and age at first assessment of 69.3 ± 8.5 years. The mean CRP was 0.33 ± 0.58 mg/dl. At follow-up (mean, 36.9 ± 27.0 months) 42.3% of MCI patients converted to dementia. Lower CSF Aβ42 (HR = 0.999, 95%CI = [0.997, 1.000], p = 0.015), lower MMSE score (HR = 0.864, 95%CI = [0.510, 1.595], p = 0.008) and lower CRP quartile (HR = 0.597, 95%CI = [0.435, 0.819], p = 0.001) were independent predictors of conversion. Conclusion CRP may add information of risk of conversion in MCI patients. Patients with lower CRP levels appear to have a more rapid conversion to AD dementia.

Neurofibrillary tangles and tau protein, the neuropathological hallmarks of Alzheimer's disease (AD), have been identified in patients with epilepsy. Tau protein was also associated with the modulation of neuronal excitability in animal models of AD.We evaluated in 292 patients with AD the association between the risk of seizure development and AD cerebrospinal fluid (CSF) biomarkers, demographic characteristics, baseline Mini-Mental State Examination (MMSE) score, comorbidities, and apolipoprotein E status.The development of seizures was associated with younger age at dementia's onset, lower baseline MMSE, and higher CSF total tau protein levels, but only MMSE (hazard ratio [HR] = 0.935; 95% confidence interval [CI] = [0.903, 0.968]; p 0.001) and CSF tau (HR = 1.001; 95%CI = [1.001, 1.002]; p = 0.001) were independent predictors on multivariate analysis.While CSF tau and lower baseline MMSE association with seizure development could in part be explained by a greater degree of cortical damage, the role of tau in the modulation of neuronal excitability may also play a role and should be further investigated.

Frontotemporal dementia (FTD) is a heterogeneous group of neurodegenerative disorders with both sporadic and genetic forms. Mutations in the progranulin gene (GRN) are a common cause of genetic FTD, causing either a behavioural presentation or, less commonly, language impairment. Presence on T2-weighted images of white matter hyperintensities (WMH) has been previously shown to be more commonly associated with GRN mutations rather than other forms of FTD. The aim of the current study was to investigate the longitudinal change in WMH and the associations of WMH burden with grey matter (GM) loss, markers of neurodegeneration and cognitive function in GRN mutation carriers. 336 participants in the Genetic FTD Initiative (GENFI) study were included in the analysis: 101 presymptomatic and 32 symptomatic GRN mutation carriers, as well as 203 mutation-negative controls. 39 presymptomatic and 12 symptomatic carriers, and 73 controls also had longitudinal data available. Participants underwent MR imaging acquisition including isotropic 1 mm T1-weighted and T2-weighted sequences. WMH were automatically segmented and locally subdivided to enable a more detailed representation of the pathology distribution. Log-transformed WMH volumes were investigated in terms of their global and regional associations with imaging measures (grey matter volumes), biomarker concentrations (plasma neurofilament light chain, NfL, and glial fibrillary acidic protein, GFAP), genetic status (TMEM106B risk genotype) and cognition (tests of executive function). Analyses revealed that WMH load was higher in both symptomatic and presymptomatic groups compared with controls and this load increased over time. In particular, lesions were seen periventricularly in frontal and occipital lobes, progressing to medial layers over time. However, there was variability in the WMH load across GRN mutation carriers - in the symptomatic group 25.0% had none/mild load, 37.5% had medium and 37.5% had a severe load - a difference not fully explained by disease duration. GM atrophy was strongly associated with WMH load both globally and in separate lobes, and increased WMH burden in the frontal, periventricular and medial regions was associated with worse executive function. Furthermore, plasma NfL and to a lesser extent GFAP concentrations were seen to be associated with increased lesion burden. Lastly, the presence of the homozygous TMEM106B rs1990622 TT risk genotypic status was associated with an increased accrual of WMH per year. In summary, WMH occur in GRN mutation carriers and accumulate over time, but are variable in their severity. They are associated with increased GM atrophy and executive dysfunction. Furthermore, their presence is associated with markers of WM damage (NfL) and astrocytosis (GFAP), whilst their accrual is modified by TMEM106B genetic status. WMH load may represent a target marker for trials of disease modifying therapies in individual patients but the variability across the GRN population would prevent use of such markers as a global outcome measure across all participants in a trial. ispartof: NEUROIMAGE-CLINICAL vol:24 ispartof: location:Netherlands status: published

Cerebrospinal fluid (CSF) 14-3-3 protein supports sporadic Creutzfeldt-Jakob (sCJD) diagnosis, but often leads to weak-positive results and lacks standardization. In this study, we explored the added diagnostic value of Total Tau (t-Tau) and phosphorylated Tau (p-Tau) in sCJD diagnosis, particularly in the cases with inconclusive 14-3-3 result. 95 definite sCJD and 287 patients without prion disease (non-CJD) were included in this study. CSF samples were collected in routine clinical diagnosis and analysed for 14-3-3 detection by Western blot (WB). CSF t-Tau and p-Tau were quantified by commercial ELISA kits and PRNP and APOE genotyping assessed by PCR-RFLP. In a regression analysis of the whole cohort, 14-3-3 protein revealed an overall accuracy of 82 % (sensitivity = 96.7 %; specificity = 75.6 %) for sCJD. Regarding 14-3-3 clear positive results, we observed no added value either of t-Tau alone or p-Tau/t-Tau ratio in the model. On the other hand, considering 14-3-3 weak-positive cases, t-Tau protein increased the overall accuracy of 14-3-3 alone from 91 to 94 % and specificity from 74 to 93 % (p

Protein 14-3-3 is a reliable marker of rapid neuronal damage, specifically increased in cerebrospinal fluid (CSF) of sporadic Creutzfeldt-Jakob disease (sCJD) patients. Its detection is usually performed by Western Blot (WB), prone to methodological issues. Our aim was to evaluate the diagnostic performance of a recently developed quantitative enzyme-linked immunosorbent (ELISA) assay for 14-3-3γ, in comparison with WB and other neurodegeneration markers. CSF samples from 145 patients with suspicion of prion disease, later classified as definite sCJD (n=72) or Non-prion diseases (Non-CJD; n=73) comprised our population. 14-3-3 protein was determined by WB and ELISA. Total Tau (t-Tau) and phosphorylated Tau (p-Tau) were also evaluated. Apolipoprotein E gene (ApoE) and prionic protein gene (PRNP) genotyping was assessed. ELISA 14-3-3γ levels were significantly increased in sCJD compared to Non-CJD patients (p

BACKGROUND: Neurofilament light chain (NfL) is a promising blood biomarker in genetic frontotemporal dementia, with elevated concentrations in symptomatic carriers of mutations in GRN, C9orf72, and MAPT. A better understanding of NfL dynamics is essential for upcoming therapeutic trials. We aimed to study longitudinal NfL trajectories in people with presymptomatic and symptomatic genetic frontotemporal dementia.METHODS: We recruited participants from 14 centres collaborating in the Genetic Frontotemporal Dementia Initiative (GENFI), which is a multicentre cohort study of families with genetic frontotemporal dementia done across Europe and Canada. Eligible participants (aged ≥18 years) either had frontotemporal dementia due to a pathogenic mutation in GRN, C9orf72, or MAPT (symptomatic mutation carriers) or were healthy at-risk first-degree relatives (either presymptomatic mutation carriers or non-carriers), and had at least two serum samples with a time interval of 6 months or more. Participants were excluded if they had neurological comorbidities that were likely to affect NfL, including cerebrovascular events. We measured NfL longitudinally in serum samples collected between June 8, 2012, and Dec 8, 2017, through follow-up visits annually or every 2 years, which also included MRI and neuropsychological assessments. Using mixed-effects models, we analysed NfL changes over time and correlated them with longitudinal imaging and clinical parameters, controlling for age, sex, and study site. The primary outcome was the course of NfL over time in the various stages of genetic frontotemporal dementia.FINDINGS: We included 59 symptomatic carriers and 149 presymptomatic carriers of a mutation in GRN, C9orf72, or MAPT, and 127 non-carriers. Nine presymptomatic carriers became symptomatic during follow-up (so-called converters). Baseline NfL was elevated in symptomatic carriers (median 52 pg/mL [IQR 24-69]) compared with presymptomatic carriers (9 pg/mL [6-13]; pINTERPRETATION: Our findings show the value of blood NfL as a disease progression biomarker in genetic frontotemporal dementia and suggest that longitudinal NfL measurements could identify mutation carriers approaching symptom onset and capture rates of brain atrophy. The characterisation of NfL over the course of disease provides valuable information for its use as a treatment effect marker.FUNDING: ZonMw and the Bluefield project.

Background: Despite having the same histopathological characteristics, early-onset and late-onset Alzheimer’s disease (AD) patients show some distinct clinical and neuropsychological profiles. Early Onset Mild Cognitive Impairment (EOMCI) is a less characterized group. The aim of this study is to characterize MCI probably due to AD in terms of the clinical, genetic, Cerebrospinal fluid (CSF) biomarkers profile and conversion rate of EOMCI, compared to the late-onset form (LOMCI). Methods: 159 MCI patients were divided in two groups: 52 EOMCI (onset < 65 years) and 107 LOMCI (onset ≥ 65 years). We investigated differences in neuropsychological scores, clinical variables, ApoE genotype, CSF biomarkers (Aβ42, t-Tau and p-Tau) in both groups. Conversion was ascertained during follow-up. Results: EOMCI showed a longer duration of symptoms prior to the first evaluation (EOMCI = 4.57 vs. LOMCI = 3.31, p = 0.008) and scored higher on the subjective memory complaints scale (9.91 vs. 7.85, p = 0.008), but performed better in brief cognitive tests (27.81 vs. 26.51, p < 0.001 in Mini-Mental State Examination; 19.84 vs. 18.67, p = 0.005 in Montreal Cognitive Assessment) than LOMCI. ApoE genotype distribution and CSF biomarker profile were similar in both groups, as was the conversion risk. Lower Aβ42 (Hazard ratio (HR): 0.998, 95% Confidence Interval (CI) = [0.996–1.000], p = 0.042), higher t-Tau levels (HR: 1.003, 95%CI = [1.000–1.005], p = 0.039) and higher scores in the Alzheimer Disease Assessment Scale-Cognitive (HR: 1.186, 95%CI = [1.083–1.299], p = 0.002) increased the risk of conversion. Discussion: Despite differences in memory performance and memory complaints, EOMCI and LOMCI seem to represent indistinct biological groups that do not have a higher risk of conversion to AD or differ in risk factors for conversion.

Background: Multiple sclerosis (MS) is an autoimmune disease characterized by inflammation and axonal degeneration of the central nervous system and a leading cause of disability in young adults. The matrix metalloproteinases in general and specially gelatinase B/metalloproteinase-9 (MMP-9) plays a role in the pathogenesis of multiple sclerosis. Objective: To investigate the presence of the MMP-9 1562 C/T polymorphism in a Portuguese population of MS patients and assess its impact in susceptibility and course of the disease. The relation of MMP-9 serum levels with the polymorphism and with clinical and therapeutic factors will also be assessed. Methods: Our study included 355 Caucasian individuals distributed as MS patients (n=169) and controls (n=186). Samples were genotyped for 1562 C/T polymorphism by PCR-RFLP analysis. MMP-9 concentration in serum was analyzed using a commercially available enzyme-linked immunosorbent assay. Results: A significant increase in T-allele frequency was found in female MS patients, but not in the total patient population. No association between the presence of the polymorphism and disease progression was found. MMP-9 serum concentrations were increased in patients, and although not influenced by the 1562 C/T polymorphism, were modified by INF-beta therapy. Conclusion: Although we did not find an association of this polymorphism with disease susceptibility or prognosis, MMP-9 appears to be a good therapeutic response marker for multiple sclerosis., Portuguese Foundation for Science and Technology (FCT) through SFRH/PROTEC/67690/2010, info:eu-repo/semantics/publishedVersion

Cerebrospinal fluid (CSF) biomarkers have been increasingly studied for dementia diagnosis, however the accuracy to distinguish between different forms of dementia is still unsatisfactory. In this study, the added value of another CSF Aβ-peptide (Aβ40), along with the core CSF markers t-Tau, p-Tau, and Aβ42, in the discrimination between two large dementia groups of Frontotemporal Lobar Degeneration (FTLD; n=107), Alzheimer's Disease (AD; n=107) and non-demented subjects (n=33) was evaluated. In FTLD, t-Tau and p-Tau were significantly increased in relation to controls, but lower than in AD, while Aβ42 was similar in FTLD and controls, but higher than in AD. Equally reduced Aβ40 levels were seen in both dementia groups, and therefore the combination of Aβ40 with core CSF biomarkers optimally discriminated FTLD and AD patients from controls. Aβ42 and t-Tau were selected as the best biomarker subset to differentiate FTLD from AD, with no added value of Aβ40 to the model. Diagnostic accuracy between FTLD and AD was still sub-optimal, with a significant percentage (23%) of FTLD patients, in particularly women, carrying an ApoE-e4 allele, showing a CSF-AD biomarkers profile. Although CSF Aβ40 does not appear to have an additional value in the distinction between FTLD and AD, it increases the discrimination between subjects with dementia from controls. A CSF-AD biomarker profile can be seen in patients with a clinical phenotype of FTLD, reinforcing the need for autopsy confirmation.

© 2015 Elsevier Inc. All rights reserved., Decreased levels of alpha-synuclein (aSyn) in cerebrospinal fluid (CSF) in Parkinson's disease and related synucleinopathies have been reported, however, not consistently in all cross-sectional studies. To test the performance of one recently released human-specific enzyme-linked immunosorbent assay (ELISA) for the quantification of aSyn in CSF, we carried out a round robin trial with 18 participating laboratories trained in CSF ELISA analyses within the BIOMARKAPD project in the EU Joint Program - Neurodegenerative Disease Research. CSF samples (homogeneous aliquots from pools) and ELISA kits (one lot) were provided centrally and data reported back to one laboratory for data analysis. Our study showed that although factors such as preanalytical sample handling and lot-to-lot variability were minimized by our study design, we identified high variation in absolute values of CSF aSyn even when the same samples and same lots of assays were applied. We further demonstrate that although absolute concentrations differ between laboratories the quantitative results are comparable. With further standardization this assay may become an attractive tool for comparing aSyn measurements in diverse settings. Recommendations for further validation experiments and improvement of the interlaboratory results obtained are given., This is an EU Joint Program – Neurodegenerative Disease Research (JPND) project. The project is supported through the following funding organizations under the aegis of JPND–www.jpnd.eu: The Alzheimer Research Foundation (SAO-FRA), Belgium (grant number S#12018); Danish Council for Strategic Research, Denmark (grant number 0603-00511B); Bundesministerium für Bildung und Forschung (BMBF), Germany (grant number OIED1203C); General Secretary of Research and Technology, Greece; Italian Ministry of Health (Ricerca Corrente), Italy; The Fundação para a Ciência e a Tecnologia, Portugal (grant numbers JPND/0004/2011, IMM/BPD/51-2013, IMM/BI/7-2013, JPND/0005/2011); Fondo de Investigaciones Sanitarias, Instituto de Salud Carlos III, Spain (grant numbers PI11/03026, PI11/03035; cofinanced by the Fondo Europeo de Desarrollo Regional); The Ministry of Education, Research and Sport of the Slovak Republic, Slovakia; The Slovenian Research Agency, Slovenia (grant number A3-0001); The Swedish Research Council, Sweden; Ministry of Education for Netherlands: ZonMw (The Netherlands Organisation for Health Research and Development), The Netherlands (grant number 629000002); The Scientific and Technological Research Council of Turkey (grant number 112S335).

Lemierre's syndrome (LS) is an uncommon but potentially life-threatening complication of an anaerobic oropharyngeal infection, affecting young adults and adolescents. The disease is characterised by a septic thrombophlebitis of the internal jugular vein and "metastatic" infections, which can be followed by fulminant sepsis and rapid death. More recently, it has been reported a recrudescence of this condition, which could be attributable to alterations in antibiotic usage patterns. The authors report the case of a LS secondary to a bout of intense cough, a cause not yet described in the literature, highlighting the importance of a quick diagnosis and the institution of an appropriate therapy.

Primary hyperparathyroidism HPT is associated with generalized skeletal changes, its full-blown osseous manifestations known as . osteitis fibrosa cystica. Fibrous dysplasia FD , a benign bone disorder, is differentiated from generalized fibrocystic disease caused by hyperparathyroidism. The classic triad of McCune-Albright syndrome includes polyostotic FD, patchy skin pigmentation, and sexual precocity. Other associated endocrinopathies are hyperthyroidism, Cushing's syndrome, acromegaly, and HPT. We describe a patient with severe generalized and focal bone lesions and sexual precocity. HPT was diagnosed and treated with persistence of cystic bone lesions. The similarities between HPT and FD are discussed, focusing on a possible genetically determined mechanism to explain the relationship between them. q 1999 Elsevier Science B.V. All rights reserved.

Made available in DSpace on 2022-01-12T17:03:35Z (GMT). No. of bitstreams: 1 8689_18502.pdf: 1107535 bytes, checksum: e24af932b755c95aa98ec90843c07e9c (MD5) Previous issue date: 2021-11-16

Dissertação de Mestrado em Família e Género Este trabalho teve como principal objetivo explorar a forma como a identidade de género tem vindo a ser representada no universo da Banda Desenhada (BD) mainstream norte – americana, de super-heróis e super-heroínas, distribuída em Portugal. Partindo das teorias de género, das teorias do construcionismo social, das várias correntes do feminismo, optámos por um estudo longitudinal, a partir de uma amostra intencional de revistas de BD (comics), produzidos e divulgados desde os anos 60 do século XX até 2017, inclusive, dos principais títulos das duas principais editoras Norte-Americanas: Marvel Comics e DC Comics. Numa abordagem metodológica mista, aplicámos as técnicas de análise de conteúdo, análise narrativa. A análise incidiu sobre a equipa de produção dos comics, em termos representatividade de género, sobre as personagens principais e as narrativas. Aplicámos entrevistas a artistas de BD, na medida em que possam ter tido influências deste tipo de BD, tenham ou não na sua agenda as questões de género. Nas conclusões finais, podemos afirmar que a forma como os estereótipos de género são transmitidos nos comics, bem como os atributos associados, são marcadamente sujeitos a influências externas e crenças individuais do corpo de produção. Contudo, verificamos, desde os anos 1960, até 2017, que as grandes editoras têm vindo a enquadrar-se nas novas realidades sociais: nas equipas de artistas insinua-se maior diversidade de género, o que gera conteúdos onde se integram e interagem personagens desafiadoras da dualidade de género e da hétero-normatividade. This thesis main goal was to understand the way has gender identity has been represented in north-american mainstream comics of super-heroes and super-heroines, distributed in Portugal. Starting from the theories of gender and feminist theories, we opted for a longitudinal study, from an intentional sample of BD magazines (comics), we opted for a longitudinal study of an intentional sample of comics produced and divulged since the 60s of the XXth century until 2017, of the main titles of the leading north-american imprints: Marvel Comics and DC Comics. In a mixed methodological approach, we applied techniques of content analysis and narrative analysis. Our analisys focused on the comics production team, in terms of its gender representation, upon the main characters and the narratives. We conducted interviews with comics artists, having or not in their agenda gender issues. In the final conclusions, we can state that the way gender stereotypes are transmitted in comics, are markedly influenced by external influences and individual beliefs in the production team. Also the major publishers have been placed in the new social realities: artistic teams gender diversified, contents and characters who are challenging gender duality and heteronormativity. N/A

Made available in DSpace on 2020-02-19T16:51:52Z (GMT). No. of bitstreams: 1 6036_12752.pdf: 1212090 bytes, checksum: 2a5188eac457aa8ca299b8564ed44fc7 (MD5) Previous issue date: 2018-03-15

Submitted by Paulo Pessoa (pfep@ubi.pt) on 2016-07-26T14:03:34Z No. of bitstreams: 1 Dissertação Fábio Augusto - vigilância à distância de um cli.pdf: 1542522 bytes, checksum: 2e4113fd39aa86325cb4a23590dc895a (MD5) Approved for entry into archive by Paulo Pessoa (pfep@ubi.pt) on 2016-07-26T14:03:51Z (GMT) No. of bitstreams: 1 Dissertação Fábio Augusto - vigilância à distância de um cli.pdf: 1542522 bytes, checksum: 2e4113fd39aa86325cb4a23590dc895a (MD5) Made available in DSpace on 2016-07-26T14:03:51Z (GMT). No. of bitstreams: 1 Dissertação Fábio Augusto - vigilância à distância de um cli.pdf: 1542522 bytes, checksum: 2e4113fd39aa86325cb4a23590dc895a (MD5) Previous issue date: 2014

Submitted by Joana Lopes Dias (jdias@ubi.pt) on 2014-12-03T16:25:40Z No. of bitstreams: 1 Dissertação Ana Crespo.pdf: 1520626 bytes, checksum: 22e91bc61c961f8d55e3f3ffd9c63381 (MD5) Made available in DSpace on 2014-12-03T16:25:40Z (GMT). No. of bitstreams: 1 Dissertação Ana Crespo.pdf: 1520626 bytes, checksum: 22e91bc61c961f8d55e3f3ffd9c63381 (MD5) Previous issue date: 2013

Submitted by Joana Lopes Dias (jdias@ubi.pt) on 2014-12-04T17:16:44Z No. of bitstreams: 2 Tese final.pdf: 1183428 bytes, checksum: 1887753e532f4d53bd22f6396c0bd2af (MD5) Anexos tese.pdf: 388920 bytes, checksum: 86e7bf38b7d29319ff1631d69f40cf23 (MD5) Made available in DSpace on 2014-12-04T17:16:44Z (GMT). No. of bitstreams: 2 Tese final.pdf: 1183428 bytes, checksum: 1887753e532f4d53bd22f6396c0bd2af (MD5) Anexos tese.pdf: 388920 bytes, checksum: 86e7bf38b7d29319ff1631d69f40cf23 (MD5) Previous issue date: 2013

Submitted by Joana Lopes Dias (jdias@ubi.pt) on 2014-12-04T16:54:10Z No. of bitstreams: 1 -Ficheiros-Reservado-DOCS-Modelo_Dissertacao.pdf: 2467112 bytes, checksum: 5acb8ecfdaa0669b89db99c5e1a1b894 (MD5) Made available in DSpace on 2014-12-04T16:54:10Z (GMT). No. of bitstreams: 1 -Ficheiros-Reservado-DOCS-Modelo_Dissertacao.pdf: 2467112 bytes, checksum: 5acb8ecfdaa0669b89db99c5e1a1b894 (MD5) Previous issue date: 2013

Submitted by Joana Lopes Dias (jdias@ubi.pt) on 2014-12-15T14:41:24Z No. of bitstreams: 30 TeseFinal.pdf: 1043153 bytes, checksum: 9825c79347542222f9c50d2e9f162eb6 (MD5) Listagem de Anexos.pdf: 120292 bytes, checksum: 08f05160398a1166a40b7fb4e48ca38f (MD5) Anexo 1.pdf: 109274 bytes, checksum: 712287e53b37ef81c1f766948b9bad80 (MD5) Anexo 2.pdf: 123605 bytes, checksum: 29143d9894515a595e11dd3c6bbb9f4b (MD5) Anexo 3.pdf: 52586 bytes, checksum: 500f8c316a012ad930c27f131a038c98 (MD5) Entrevista1.pdf: 222367 bytes, checksum: 6abb41b0e534d5e62eb82e75c53037a4 (MD5) Entrevista2.pdf: 212783 bytes, checksum: 545626fe55150cc0fc3d58ada703f997 (MD5) Entrevista3.pdf: 156407 bytes, checksum: e461a5e90b4ca18a16919a83a79f6c67 (MD5) Entrevista4.pdf: 251502 bytes, checksum: bf3c23f9ebfa10fbf4dc2ad2b6c782bb (MD5) Entrevista5 .pdf: 153634 bytes, checksum: eafc212e952342861345b18b2c30b710 (MD5) Entrevista6.pdf: 149153 bytes, checksum: a92426ad4ebf2e353eb23e76f0c98534 (MD5) Entrevista7.pdf: 159368 bytes, checksum: 1e2e02d885473e9a4d0a929d3c810cd7 (MD5) Entrevista8.pdf: 175961 bytes, checksum: 5c235f04e4a3f6e25fac5150b0803b17 (MD5) Entrevista9.pdf: 152617 bytes, checksum: a6bfb23d9e8760a461f06d85ca507c66 (MD5) Entrevista10.pdf: 150712 bytes, checksum: 1ce733b9aa79cd407a035a4ecac39eea (MD5) Entrevista11.pdf: 144554 bytes, checksum: 8178aa96af69f0fcf31e3c18c73530ba (MD5) Entrevista12.pdf: 150760 bytes, checksum: 8ebc4f8d47179a895eeacfc2f1a3a2d0 (MD5) Entrevista13.pdf: 240457 bytes, checksum: c99e12a4fef53b29314aa73ad897423a (MD5) Entrevista14.pdf: 219659 bytes, checksum: af68d02c61364265f2f44fabf4b2e957 (MD5) Entrevista15.pdf: 166773 bytes, checksum: de68c8b3bd29c21ce6b4a05cf0723049 (MD5) Entrevista16.pdf: 87514 bytes, checksum: 44964e3d1534e84bf69a3d8d068948d3 (MD5) Entrevista17.pdf: 170726 bytes, checksum: 14c69d92bcae1b7be648aaf63a1bc332 (MD5) Entrevista18.pdf: 150164 bytes, checksum: d8b70e7e1245f717867ef2612975a0b2 (MD5) Entrevista19.pdf: 84912 bytes, checksum: 97113c0d9357c081fd0f8c6e280acf4d (MD5) Entrevista20.pdf: 148194 bytes, checksum: 230731b21c6ade1b6a6a5aa5ed701b9c (MD5) Entrevista21.pdf: 145033 bytes, checksum: 2a0f7df65bfed19eaee7eb142d0e0ec0 (MD5) Entrevista22.pdf: 154090 bytes, checksum: a430417ed3b52a3cba29e97bc8e2d4fc (MD5) Entrevista23.pdf: 161995 bytes, checksum: 3d772c559be3e99d369186f6147aaf78 (MD5) Entrevista24.pdf: 158985 bytes, checksum: 8eb03f1fb7189ca0a95fb65dd6e325ae (MD5) Entrevista25.pdf: 157058 bytes, checksum: 57ed460144d7ee1083ab18a0ef58020f (MD5) Made available in DSpace on 2014-12-15T14:41:24Z (GMT). No. of bitstreams: 30 TeseFinal.pdf: 1043153 bytes, checksum: 9825c79347542222f9c50d2e9f162eb6 (MD5) Listagem de Anexos.pdf: 120292 bytes, checksum: 08f05160398a1166a40b7fb4e48ca38f (MD5) Anexo 1.pdf: 109274 bytes, checksum: 712287e53b37ef81c1f766948b9bad80 (MD5) Anexo 2.pdf: 123605 bytes, checksum: 29143d9894515a595e11dd3c6bbb9f4b (MD5) Anexo 3.pdf: 52586 bytes, checksum: 500f8c316a012ad930c27f131a038c98 (MD5) Entrevista1.pdf: 222367 bytes, checksum: 6abb41b0e534d5e62eb82e75c53037a4 (MD5) Entrevista2.pdf: 212783 bytes, checksum: 545626fe55150cc0fc3d58ada703f997 (MD5) Entrevista3.pdf: 156407 bytes, checksum: e461a5e90b4ca18a16919a83a79f6c67 (MD5) Entrevista4.pdf: 251502 bytes, checksum: bf3c23f9ebfa10fbf4dc2ad2b6c782bb (MD5) Entrevista5 .pdf: 153634 bytes, checksum: eafc212e952342861345b18b2c30b710 (MD5) Entrevista6.pdf: 149153 bytes, checksum: a92426ad4ebf2e353eb23e76f0c98534 (MD5) Entrevista7.pdf: 159368 bytes, checksum: 1e2e02d885473e9a4d0a929d3c810cd7 (MD5) Entrevista8.pdf: 175961 bytes, checksum: 5c235f04e4a3f6e25fac5150b0803b17 (MD5) Entrevista9.pdf: 152617 bytes, checksum: a6bfb23d9e8760a461f06d85ca507c66 (MD5) Entrevista10.pdf: 150712 bytes, checksum: 1ce733b9aa79cd407a035a4ecac39eea (MD5) Entrevista11.pdf: 144554 bytes, checksum: 8178aa96af69f0fcf31e3c18c73530ba (MD5) Entrevista12.pdf: 150760 bytes, checksum: 8ebc4f8d47179a895eeacfc2f1a3a2d0 (MD5) Entrevista13.pdf: 240457 bytes, checksum: c99e12a4fef53b29314aa73ad897423a (MD5) Entrevista14.pdf: 219659 bytes, checksum: af68d02c61364265f2f44fabf4b2e957 (MD5) Entrevista15.pdf: 166773 bytes, checksum: de68c8b3bd29c21ce6b4a05cf0723049 (MD5) Entrevista16.pdf: 87514 bytes, checksum: 44964e3d1534e84bf69a3d8d068948d3 (MD5) Entrevista17.pdf: 170726 bytes, checksum: 14c69d92bcae1b7be648aaf63a1bc332 (MD5) Entrevista18.pdf: 150164 bytes, checksum: d8b70e7e1245f717867ef2612975a0b2 (MD5) Entrevista19.pdf: 84912 bytes, checksum: 97113c0d9357c081fd0f8c6e280acf4d (MD5) Entrevista20.pdf: 148194 bytes, checksum: 230731b21c6ade1b6a6a5aa5ed701b9c (MD5) Entrevista21.pdf: 145033 bytes, checksum: 2a0f7df65bfed19eaee7eb142d0e0ec0 (MD5) Entrevista22.pdf: 154090 bytes, checksum: a430417ed3b52a3cba29e97bc8e2d4fc (MD5) Entrevista23.pdf: 161995 bytes, checksum: 3d772c559be3e99d369186f6147aaf78 (MD5) Entrevista24.pdf: 158985 bytes, checksum: 8eb03f1fb7189ca0a95fb65dd6e325ae (MD5) Entrevista25.pdf: 157058 bytes, checksum: 57ed460144d7ee1083ab18a0ef58020f (MD5) Previous issue date: 2012

Submitted by Joana Lopes Dias (jdias@ubi.pt) on 2014-12-15T15:31:53Z No. of bitstreams: 6 dissertação pdf final (1).pdf: 979952 bytes, checksum: 63e9c91ee4175d9fb889c3e080b7dad5 (MD5) Anexos - Guiões.pdf: 144111 bytes, checksum: 32339e687c2dd2cedf3792ccaed80775 (MD5) Sinopse I idosos institucionalizados.pdf: 98097 bytes, checksum: e394adb4a4f60a3cb5bc485d70ddefcc (MD5) Sinopse II Idosos Não Institucionalizados.pdf: 95040 bytes, checksum: e90b7236ce96fb989906202e78ef1fe6 (MD5) Sinopse III directoras técnicas.pdf: 229660 bytes, checksum: d4157b01d8e8d91e46cf149b99fa01b5 (MD5) Sinopse IV Familiares de idosos institucionalizados.pdf: 127930 bytes, checksum: 29955e00b660be110096c002588a869b (MD5) Made available in DSpace on 2014-12-15T15:31:53Z (GMT). No. of bitstreams: 6 dissertação pdf final (1).pdf: 979952 bytes, checksum: 63e9c91ee4175d9fb889c3e080b7dad5 (MD5) Anexos - Guiões.pdf: 144111 bytes, checksum: 32339e687c2dd2cedf3792ccaed80775 (MD5) Sinopse I idosos institucionalizados.pdf: 98097 bytes, checksum: e394adb4a4f60a3cb5bc485d70ddefcc (MD5) Sinopse II Idosos Não Institucionalizados.pdf: 95040 bytes, checksum: e90b7236ce96fb989906202e78ef1fe6 (MD5) Sinopse III directoras técnicas.pdf: 229660 bytes, checksum: d4157b01d8e8d91e46cf149b99fa01b5 (MD5) Sinopse IV Familiares de idosos institucionalizados.pdf: 127930 bytes, checksum: 29955e00b660be110096c002588a869b (MD5) Previous issue date: 2012

Submitted by Joana Lopes Dias (jdias@ubi.pt) on 2014-10-14T18:15:14Z No. of bitstreams: 8 Dissertação.pdf: 632068 bytes, checksum: 3337941fe1ae77648366399f3d9575ad (MD5) Guião entrevista aos pais cuidadores.pdf: 44535 bytes, checksum: 23c59bf5be787a6f337eb8c351eaa480 (MD5) Guião entrevista às pessoas com deficiência.pdf: 47092 bytes, checksum: 960130bb74d4c272eb638e4d95e30017 (MD5) Sinopse 1- Percepções.pdf: 43979 bytes, checksum: e5e441bb0248988335c20b72177de814 (MD5) Sinopse 2 - Educação.pdf: 45950 bytes, checksum: 5d480e9af63f5961c829a776725e2fa3 (MD5) Sinopse 3 - Saúde.pdf: 40772 bytes, checksum: 49a31033feddaec36a89fb3f12f906b5 (MD5) Sinopse 4 - Acção Social.pdf: 36263 bytes, checksum: 58e1b476dc0aad8df615e839bf8d7b8e (MD5) Sinopse 5 - Condição de Vida.pdf: 47422 bytes, checksum: 9fb3e7d5e21bb13d544c50463748b5aa (MD5) Made available in DSpace on 2014-10-14T18:15:14Z (GMT). No. of bitstreams: 8 Dissertação.pdf: 632068 bytes, checksum: 3337941fe1ae77648366399f3d9575ad (MD5) Guião entrevista aos pais cuidadores.pdf: 44535 bytes, checksum: 23c59bf5be787a6f337eb8c351eaa480 (MD5) Guião entrevista às pessoas com deficiência.pdf: 47092 bytes, checksum: 960130bb74d4c272eb638e4d95e30017 (MD5) Sinopse 1- Percepções.pdf: 43979 bytes, checksum: e5e441bb0248988335c20b72177de814 (MD5) Sinopse 2 - Educação.pdf: 45950 bytes, checksum: 5d480e9af63f5961c829a776725e2fa3 (MD5) Sinopse 3 - Saúde.pdf: 40772 bytes, checksum: 49a31033feddaec36a89fb3f12f906b5 (MD5) Sinopse 4 - Acção Social.pdf: 36263 bytes, checksum: 58e1b476dc0aad8df615e839bf8d7b8e (MD5) Sinopse 5 - Condição de Vida.pdf: 47422 bytes, checksum: 9fb3e7d5e21bb13d544c50463748b5aa (MD5) Previous issue date: 2010

Submitted by Joana Lopes Dias (jdias@ubi.pt) on 2014-10-14T18:37:09Z No. of bitstreams: 1 Tese Mestrado - Filipa Manteigas.pdf: 1277166 bytes, checksum: b93ddbc86eee53ff809902919bdde3f7 (MD5) Made available in DSpace on 2014-10-14T18:37:09Z (GMT). No. of bitstreams: 1 Tese Mestrado - Filipa Manteigas.pdf: 1277166 bytes, checksum: b93ddbc86eee53ff809902919bdde3f7 (MD5) Previous issue date: 2010

Submitted by Joana Lopes Dias (jdias@ubi.pt) on 2014-10-14T17:00:13Z No. of bitstreams: 1 Bruno Machado - Empowerment in Microfinance TESE.pdf: 2455719 bytes, checksum: 13989f9dac302258c9b5384082153a3c (MD5) Made available in DSpace on 2014-10-14T17:00:13Z (GMT). No. of bitstreams: 1 Bruno Machado - Empowerment in Microfinance TESE.pdf: 2455719 bytes, checksum: 13989f9dac302258c9b5384082153a3c (MD5) Previous issue date: 2010

Submitted by Joana Lopes Dias (jdias@ubi.pt) on 2014-10-14T10:53:38Z No. of bitstreams: 1 Dissertação_de_Mestrado_-_A_Participação_nas_Redes_Sociais.pdf: 790491 bytes, checksum: b9972d2de484d2fd207e37ebd2231d30 (MD5) Made available in DSpace on 2014-10-14T10:53:38Z (GMT). No. of bitstreams: 1 Dissertação_de_Mestrado_-_A_Participação_nas_Redes_Sociais.pdf: 790491 bytes, checksum: b9972d2de484d2fd207e37ebd2231d30 (MD5) Previous issue date: 2008