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Sökning: WFRF:(Herholz K)

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1.
  • Frisoni, G. B., et al. (författare)
  • Strategic roadmap for an early diagnosis of Alzheimer's disease based on biomarkers
  • 2017
  • Ingår i: Lancet Neurology. - : Lancet Ltd. - 1474-4422 .- 1474-4465. ; 16:8, s. 661-676
  • Tidskriftsartikel (refereegranskat)abstract
    • The diagnosis of Alzheimer's disease can be improved by the use of biological measures. Biomarkers of functional impairment, neuronal loss, and protein deposition that can be assessed by neuroimaging (ie, MRI and PET) or CSF analysis are increasingly being used to diagnose Alzheimer's disease in research studies and specialist clinical settings. However, the validation of the clinical usefulness of these biomarkers is incomplete, and that is hampering reimbursement for these tests by health insurance providers, their widespread clinical implementation, and improvements in quality of health care. We have developed a strategic five-phase roadmap to foster the clinical validation of biomarkers in Alzheimer's disease, adapted from the approach for cancer biomarkers. Sufficient evidence of analytical validity (phase 1 of a structured framework adapted from oncology) is available for all biomarkers, but their clinical validity (phases 2 and 3) and clinical utility (phases 4 and 5) are incomplete. To complete these phases, research priorities include the standardisation of the readout of these assays and thresholds for normality, the evaluation of their performance in detecting early disease, the development of diagnostic algorithms comprising combinations of biomarkers, and the development of clinical guidelines for the use of biomarkers in qualified memory clinics.
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2.
  • Botvinik-Nezer, Rotem, et al. (författare)
  • Variability in the analysis of a single neuroimaging dataset by many teams
  • 2020
  • Ingår i: Nature. - : Nature Publishing Group. - 0028-0836 .- 1476-4687. ; 582, s. 84-88
  • Tidskriftsartikel (refereegranskat)abstract
    • Data analysis workflows in many scientific domains have become increasingly complex and flexible. Here we assess the effect of this flexibility on the results of functional magnetic resonance imaging by asking 70 independent teams to analyse the same dataset, testing the same 9 ex-ante hypotheses(1). The flexibility of analytical approaches is exemplified by the fact that no two teams chose identical workflows to analyse the data. This flexibility resulted in sizeable variation in the results of hypothesis tests, even for teams whose statistical maps were highly correlated at intermediate stages of the analysis pipeline. Variation in reported results was related to several aspects of analysis methodology. Notably, a meta-analytical approach that aggregated information across teams yielded a significant consensus in activated regions. Furthermore, prediction markets of researchers in the field revealed an overestimation of the likelihood of significant findings, even by researchers with direct knowledge of the dataset(2-5). Our findings show that analytical flexibility can have substantial effects on scientific conclusions, and identify factors that may be related to variability in the analysis of functional magnetic resonance imaging. The results emphasize the importance of validating and sharing complex analysis workflows, and demonstrate the need for performing and reporting multiple analyses of the same data. Potential approaches that could be used to mitigate issues related to analytical variability are discussed. The results obtained by seventy different teams analysing the same functional magnetic resonance imaging dataset show substantial variation, highlighting the influence of analytical choices and the importance of sharing workflows publicly and performing multiple analyses.
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4.
  • Malmström, Rickard E., et al. (författare)
  • Dabigatran - a case history demonstrating the need for comprehensive approaches to optimize the use of new drugs
  • 2013
  • Ingår i: Frontiers in Pharmacology. - : FRONTIERS RESEARCH FOUNDATION. - 1663-9812 .- 1663-9812. ; 4
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: There are potential conflicts between authorities and companies to fund new premium priced drugs especially where there are safety and/or budget concerns. Dabigatran, a new oral anticoagulant for the prevention of stroke in patients with non-valvular atrial fibrillation (AF), exemplifies this issue. Whilst new effective treatments are needed, there are issues in the elderly with dabigatran due to variable drug concentrations, no known antidote and dependence on renal elimination. Published studies have shown dabigatran to be cost-effective but there are budget concerns given the prevalence of AF. There are also issues with potentially re-designing anticoagulant services. This has resulted in activities across countries to better manage its use. Objective: To (i) review authority activities in over 30 countries and regions, (ii) use the findings to develop new models to better manage the entry of new drugs, and (iii) review the implications for all major stakeholder groups. Methodology: Descriptive review and appraisal of activities regarding dabigatran and the development of guidance for groups through an iterative process. Results: There has been a plethora of activities among authorities to manage the prescribing of dabigatran including extensive pre-launch activities, risk sharing arrangements, prescribing restrictions, and monitoring of prescribing post-launch. Reimbursement has been denied in some countries due to concerns with its budget impact and/or excessive bleeding. Development of a new model and future guidance is proposed to better manage the entry of new drugs, centering on three pillars of pre-, pen-, and post-launch activities. Conclusion: Models for introducing new drugs are essential to optimize their prescribing especially where there are concerns. Without such models, new drugs may be withdrawn prematurely and/or struggle for funding.
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5.
  • Vergallo, A., et al. (författare)
  • Association of plasma YKL-40 with brain amyloid-β levels, memory performance, and sex in subjective memory complainers
  • 2020
  • Ingår i: Neurobiology of Aging. - 0197-4580. ; 96, s. 22-32
  • Tidskriftsartikel (refereegranskat)abstract
    • Neuroinflammation, a key early pathomechanistic alteration of Alzheimer's disease, may represent either a detrimental or a compensatory mechanism or both (according to the disease stage). YKL-40, a glycoprotein highly expressed in differentiated glial cells, is a candidate biomarker for in vivo tracking neuroinflammation in humans. We performed a longitudinal study in a monocentric cohort of cognitively healthy individuals at risk for Alzheimer's disease exploring whether age, sex, and the apolipoprotein E ε4 allele affect plasma YKL-40 concentrations. We investigated whether YKL-40 is associated with brain amyloid-β (Aβ) deposition, neuronal activity, and neurodegeneration as assessed via neuroimaging biomarkers. Finally, we investigated whether YKL-40 may predict cognitive performance. We found an age-associated increase of YKL-40 and observed that men display higher concentrations than women, indicating a potential sexual dimorphism. Moreover, YKL-40 was positively associated with memory performance and negatively associated with brain Aβ deposition (but not with metabolic signal). Consistent with translational studies, our results suggest a potentially protective effect of glia on incipient brain Aβ accumulation and neuronal homeostasis. © 2020 Elsevier Inc.
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7.
  • Godman, Brian, et al. (författare)
  • Dabigatran - a continuing exemplar case history demonstrating the need for comprehensive models to optimize the utilization of new drugs
  • 2014
  • Ingår i: Frontiers in Pharmacology. - 1663-9812 .- 1663-9812. ; 5
  • Forskningsöversikt (refereegranskat)abstract
    • Background: There are potential conflicts between authorities and companies to fund new premium priced drugs especially where there are effectiveness, safety and/or budget concerns. Dabigatran, a new oral anticoagulant for the prevention of stroke in patients with non-valvular atrial fibrillation (AF), exemplifies this issue. Whilst new effective treatments are needed, there are issues in the elderly with dabigatran due to variable drug concentrations, no known antidote and dependence on renal elimination. Published studies showed dabigatran to be cost-effective but there are budget concerns given the prevalence of AF. These concerns resulted in extensive activities pre- to post-launch to manage its introduction. Objective: To (i) review authority activities across countries, (ii) use the findings to develop new models to better manage the entry of new drugs, and (iii) review the implications based on post-launch activities. Methodology: (i) Descriptive review and appraisal of activities regarding dabigatran, (ii) development of guidance for key stakeholder groups through an iterative process, (iii) refining guidance following post launch studies. Results: Plethora of activities to manage dabigatran including extensive pre-launch activities, risk sharing arrangements, prescribing restrictions and monitoring of prescribing post launch. Reimbursement has been denied in some countries due to concerns with its budget impact and/or excessive bleeding. Development of a new model and future guidance is proposed to better manage the entry of new drugs, centering on three pillars of pre-, pen-, and post-launch activities. Post-launch activities include increasing use of patient registries to monitor the safety and effectiveness of new drugs in clinical practice. Conclusion: Models for introducing new drugs are essential to optimize their prescribing especially where concerns. Without such models, new drugs may be withdrawn prematurely and/or struggle for funding.
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8.
  • Nordberg, Agneta, et al. (författare)
  • A European multicentre PET study of fibrillar amyloid in Alzheimer's disease
  • 2013
  • Ingår i: European Journal of Nuclear Medicine and Molecular Imaging. - 1619-7070 .- 1619-7089. ; 40:1, s. 104-114
  • Tidskriftsartikel (refereegranskat)abstract
    • Amyloid PET tracers have been developed for in vivo detection of brain fibrillar amyloid deposition in Alzheimer's disease (AD). To serve as an early biomarker in AD the amyloid PET tracers need to be analysed in multicentre clinical studies. In this study 238 [C-11]Pittsburgh compound-B (PIB) datasets from five different European centres were pooled. Of these 238 datasets, 18 were excluded, leaving [C-11]PIB datasets from 97 patients with clinically diagnosed AD (mean age 69 +/- 8 years), 72 patients with mild cognitive impairment (MCI; mean age 67.5 +/- 8 years) and 51 healthy controls (mean age 67.4 +/- 6 years) available for analysis. Of the MCI patients, 64 were longitudinally followed for 28 +/- 15 months. Most participants (175 out of 220) were also tested for apolipoprotein E (ApoE) genotype. [C-11]PIB retention in the neocortical and subcortical brain regions was significantly higher in AD patients than in age-matched controls. Intermediate [C-11]PIB retention was observed in MCI patients, with a bimodal distribution (64 % MCI PIB-positive and 36 % MCI PIB-negative), which was significantly different the pattern in both the AD patients and controls. Higher [C-11]PIB retention was observed in MCI ApoE epsilon 4 carriers compared to non-ApoE epsilon 4 carriers (p < 0.005). Of the MCI PIB-positive patients, 67 % had converted to AD at follow-up while none of the MCI PIB-negative patients converted. This study demonstrated the robustness of [C-11]PIB PET as a marker of neocortical fibrillar amyloid deposition in brain when assessed in a multicentre setting. MCI PIB-positive patients showed more severe memory impairment than MCI PIB-negative patients and progressed to AD at an estimated rate of 25 % per year. None of the MCI PIB-negative patients converted to AD, and thus PIB negativity had a 100 % negative predictive value for progression to AD. This supports the notion that PIB-positive scans in MCI patients are an indicator of prodromal AD.
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9.
  • Sehlin, Dag, 1976-, et al. (författare)
  • Engineered antibodies : new possibilities for brain PET?
  • 2019
  • Ingår i: European Journal of Nuclear Medicine and Molecular Imaging. - : SPRINGER. - 1619-7070 .- 1619-7089. ; 46:13, s. 2848-2858
  • Forskningsöversikt (refereegranskat)abstract
    • Almost 50 million people worldwide are affected by Alzheimer's disease (AD), the most common neurodegenerative disorder. Development of disease-modifying therapies would benefit from reliable, non-invasive positron emission tomography (PET) biomarkers for early diagnosis, monitoring of disease progression, and assessment of therapeutic effects. Traditionally, PET ligands have been based on small molecules that, with the right properties, can penetrate the blood-brain barrier (BBB) and visualize targets in the brain. Recently a new class of PET ligands based on antibodies have emerged, mainly in applications related to cancer. While antibodies have advantages such as high specificity and affinity, their passage across the BBB is limited. Thus, to be used as brain PET ligands, antibodies need to be modified for active transport into the brain. Here, we review the development of radioligands based on antibodies for visualization of intrabrain targets. We focus on antibodies modified into a bispecific format, with the capacity to undergo transferrin receptor 1 (TfR1)-mediated transcytosis to enter the brain and access pathological proteins, e.g. amyloid-beta. A number of such antibody ligands have been developed, displaying differences in brain uptake, pharmacokinetics, and ability to bind and visualize the target in the brain of transgenic mice. Potential pathological changes related to neurodegeneration, e.g. misfolded proteins and neuroinflammation, are suggested as future targets for this novel type of radioligand. Challenges are also discussed, such as the temporal match of radionuclide half-life with the ligand's pharmacokinetic profile and translation to human use. In conclusion, brain PET imaging using bispecific antibodies, modified for receptor-mediated transcytosis across the BBB, is a promising method for specifically visualizing molecules in the brain that are difficult to target with traditional small molecule ligands.
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10.
  • Vergallo, A., et al. (författare)
  • Plasma amyloid beta 40/42 ratio predicts cerebral amyloidosis in cognitively normal individuals at risk for Alzheimer's disease
  • 2019
  • Ingår i: Alzheimers & Dementia. - 1552-5260. ; 15:6, s. 764-775
  • Tidskriftsartikel (refereegranskat)abstract
    • Introduction: Blood-based biomarkers of pathophysiological brain amyloid beta (A beta) accumulation, particularly for preclinical target and large-scale interventions, are warranted to effectively enrich Alzheimer's disease clinical trials and management. Methods: We investigated whether plasma concentrations of the A beta(1-40)/A beta(1-42) ratio, assessed using the single-molecule array (Simoa) immunoassay, may predict brain A beta positron emission tomography status in a large-scale longitudinal monocentric cohort (N = 276) of older individuals with subjective memory complaints. We performed a hypothesis-driven investigation followed by a no-apriori hypothesis study using machine learning. Results: The receiver operating characteristic curve and machine learning showed a balanced accuracy of 76.5% and 81%, respectively, for the plasma A beta(1-40)/A beta(1-42) ratio. The accuracy is not affected by the apolipoprotein E (APOE) epsilon 4 allele, sex, or age. Discussion: Our results encourage an independent validation cohort study to confirm the indication that the plasma A beta(1-40)/A beta(1-42) ratio, assessed via Simoa, may improve future standard of care and clinical trial design. (C) 2019 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved.
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