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| 2. |
- De Wert, G., et al.
(författare)
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Responsible innovation in human germline gene editing : Background document to the recommendations of ESHG and ESHRE
- 2018
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Ingår i: European Journal of Human Genetics. - : Nature Publishing Group. - 1018-4813 .- 1476-5438. ; 26:4, s. 450-470
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Tidskriftsartikel (refereegranskat)abstract
- Technological developments in gene editing raise high expectations for clinical applications, including editing of the germline. The European Society of Human Reproduction and Embryology (ESHRE) and the European Society of Human Genetics (ESHG) together developed a Background document and Recommendations to inform and stimulate ongoing societal debates. This document provides the background to the Recommendations. Germline gene editing is currently not allowed in many countries. This makes clinical applications in these countries impossible now, even if germline gene editing would become safe and effective. What were the arguments behind this legislation, and are they still convincing? If a technique could help to avoid serious genetic disorders, in a safe and effective way, would this be a reason to reconsider earlier standpoints? This Background document summarizes the scientific developments and expectations regarding germline gene editing, legal regulations at the European level, and ethics for three different settings (basic research, preclinical research and clinical applications). In ethical terms, we argue that the deontological objections (e.g., gene editing goes against nature) do not seem convincing while consequentialist objections (e.g., safety for the children thus conceived and following generations) require research, not all of which is allowed in the current legal situation in European countries. Development of this Background document and Recommendations reflects the responsibility to help society understand and debate the full range of possible implications of the new technologies, and to contribute to regulations that are adapted to the dynamics of the field while taking account of ethical considerations and societal concerns.
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| 3. |
- Janelidze, S., et al.
(författare)
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Head-to-Head Comparison of 8 Plasma Amyloid-beta 42/40 Assays in Alzheimer Disease
- 2021
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Ingår i: Jama Neurology. - : American Medical Association (AMA). - 2168-6149. ; 78:11, s. 1375-1382
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Tidskriftsartikel (refereegranskat)abstract
- IMPORTANCE Blood-based tests for brain amyloid-beta (A beta) pathology are needed for widespread implementation of Alzheimer disease (AD) biomarkers in clinical care and to facilitate patient screening and monitoring of treatment responses in clinical trials. OBJECTIVE To compare the performance of plasma A beta 42/40 measured using 8 different A beta assays when detecting abnormal brain A beta status in patients with early AD. DESIGN, SETTING, AND PARTICIPANTS This study included 182 cognitively unimpaired participants and 104 patients with mild cognitive impairment from the BioFINDER cohort who were enrolled at 3 different hospitals in Sweden and underwent A beta positron emission tomography (PET) imaging and cerebrospinal fluid (CSF) and plasma collection from 2010 to 2014. Plasma A beta 42/40 was measured using an immunoprecipitation-coupled mass spectrometry developed at Washington University (IP-MS-WashU), antibody-free liquid chromatography MS developed by Araclon (LC-MS-Arc), and immunoassays from Roche Diagnostics (IA-Elc); Euroimmun (IA-EI); and Amsterdam University Medical Center, ADx Neurosciences, and Quanterix (IA-N4PE). Plasma A beta 42/40 was also measured using an IP-MS-based method from Shimadzu in 200 participants (IP-MS-Shim) and an IP-MS-based method from the University of Gothenburg (IP-MS-UGOT) and another immunoassay from Quanterix (IA-Quan) among 227 participants. For validation, 122 participants (51 cognitively normal, 51 with mild cognitive impairment, and 20 with AD dementia) were included from the Alzheimer Disease Neuroimaging Initiative who underwent A beta-PET and plasma A beta assessments using IP-MS-WashU, IP-MS-Shim, IP-MS-UGOT, IA-Elc, IA-N4PE, and IA-Quan assays. MAIN OUTCOMES AND MEASURES Discriminative accuracy of plasma A beta 42/40 quantified using 8 different assays for abnormal CSF A beta 42/40 and A beta-PET status. RESULTS A total of 408 participants were included in this study. In the BioFINDER cohort, the mean (SD) age was 71.6 (5.6) years and 49.3% of the cohort were women. When identifying participants with abnormal CSF A beta 42/40 in the whole cohort, plasma IP-MS-WashU A beta 42/40 showed significantly higher accuracy (area under the receiver operating characteristic curve [AUC], 0.86; 95% CI, 0.81-0.90) than LC-MS-Arc A beta 42/40, IA-Elc A beta 42/40, IA-EI A beta 42/40, and IA-N4PE A beta 42/40 (AUC range, 0.69-0.78; P < .05). Plasma IP-MS-WashU A beta 42/40 performed significantly better than IP-MS-UGOT A beta 42/40 and IA-Quan A beta 42/40 (AUC, 0.84 vs 0.68 and 0.64, respectively; P < .001), while there was no difference in the AUCs between IP-MS-WashU A beta 42/40 and IP-MS-Shim A beta 42/40 (0.87 vs 0.83; P = .16) in the 2 subcohorts where these biomarkers were available. The results were similar when using A beta-PET as outcome. Plasma IPMS-WashU A beta 42/40 and IPMS-Shim A beta 42/40 showed highest coefficients for correlations with CSF A beta 42/40 (r range, 0.56-0.65). The BioFINDER results were replicated in the Alzheimer Disease Neuroimaging Initiative cohort (mean [SD] age, 72.4 [5.4] years; 43.4% women), where the IP-MS-WashU assay performed significantly better than the IP-MS-UGOT, IA-Elc, IA-N4PE, and IA-Quan assays but not the IP-MS-Shim assay. CONCLUSIONS AND RELEVANCE The results from 2 independent cohorts indicate that certain MS-based methods performed better than most of the immunoassays for plasma A beta 42/40 when detecting brain A beta pathology.
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| 4. |
- Janelidze, Shorena, et al.
(författare)
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Plasma P-tau181 in Alzheimer's disease: relationship to other biomarkers, differential diagnosis, neuropathology and longitudinal progression to Alzheimer's dementia
- 2020
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Ingår i: Nature Medicine. - : Springer Science and Business Media LLC. - 1078-8956 .- 1546-170X. ; 26, s. 379-386
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Tidskriftsartikel (refereegranskat)abstract
- Plasma phosphorylated tau181 (P-tau181) might be increased in Alzheimer's disease (AD), but its usefulness for differential diagnosis and prognosis is unclear. We studied plasma P-tau181 in three cohorts, with a total of 589 individuals, including cognitively unimpaired participants and patients with mild cognitive impairment (MCI), AD dementia and non-AD neurodegenerative diseases. Plasma P-tau181 was increased in preclinical AD and further increased at the MCI and dementia stages. It correlated with CSF P-tau181 and predicted positive Tau positron emission tomography (PET) scans (area under the curve (AUC) = 0.87-0.91 for different brain regions). Plasma P-tau181 differentiated AD dementia from non-AD neurodegenerative diseases with an accuracy similar to that of Tau PET and CSF P-tau181 (AUC = 0.94-0.98), and detected AD neuropathology in an autopsy-confirmed cohort. High plasma P-tau181 was associated with subsequent development of AD dementia in cognitively unimpaired and MCI subjects. In conclusion, plasma P-tau181 is a noninvasive diagnostic and prognostic biomarker of AD, which may be useful in clinical practice and trials. Plasma P-tau18 level increased with progression of Alzheimer's disease (AD) and differentiated AD dementia from other neurodegenerative diseases, supporting its further development as a blood-based biomarker for AD.
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| 5. |
- Palmqvist, Sebastian, et al.
(författare)
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An accurate fully automated panel of plasma biomarkers for Alzheimer's disease
- 2023
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Ingår i: Alzheimers & Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 19:4, s. 1204-1215
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Tidskriftsartikel (refereegranskat)abstract
- Introduction There is a great need for fully automated plasma assays that can measure amyloid beta (A beta) pathology and predict future Alzheimer's disease (AD) dementia. Methods Two cohorts (n = 920) were examined: Panel A+ (n = 32 cognitively unimpaired [CU], n = 106 mild cognitive impairment [MCI], and n = 89 AD) and BioFINDER-1 (n = 461 CU, n = 232 MCI). Plasma A beta 42/A beta 40, phosphorylated tau (p-tau)181, two p-tau217 variants, ApoE4 protein, neurofilament light, and GFAP were measured using Elecsys prototype immunoassays. Results The best biomarker for discriminating A beta-positive versus A beta-negative participants was A beta 42/A beta 40 (are under the curve [AUC] 0.83-0.87). Combining A beta 42/A beta 40, p-tau181, and ApoE4 improved the AUCs significantly (0.90 to 0.93; P< 0.01). Adding additional biomarkers had marginal effects (Delta AUC <= 0.01). In BioFINDER, p-tau181, p-tau217, and ApoE4 predicted AD dementia within 6 years in CU (AUC 0.88) and p-tau181, p-tau217, and A beta 42/A beta 40 in MCI (AUC 0.87). Discussion The high accuracies for A beta pathology and future AD dementia using fully automated instruments are promising for implementing plasma biomarkers in clinical trials and clinical routine.
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| 6. |
- Palmqvist, Sebastian, et al.
(författare)
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Cerebrospinal fluid and plasma biomarker trajectories with increasing amyloid deposition in Alzheimer's disease
- 2019
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Ingår i: Embo Molecular Medicine. - : EMBO. - 1757-4676 .- 1757-4684. ; 11:12
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Tidskriftsartikel (refereegranskat)abstract
- Failures in Alzheimer's disease (AD) drug trials highlight the need to further explore disease mechanisms and alterations of biomarkers during the development of AD. Using cross-sectional data from 377 participants in the BioFINDER study, we examined seven cerebrospinal fluid (CSF) and six plasma biomarkers in relation to beta-amyloid (A beta) PET uptake to understand their evolution during AD. In CSF, A beta 42 changed first, closely followed by A beta 42/A beta 40, phosphorylated-tau (P-tau), and total-tau (T-tau). CSF neurogranin, YKL-40, and neurofilament light increased after the point of A beta PET positivity. The findings were replicated using A beta 42, A beta 40, P-tau, and T-tau assays from five different manufacturers. Changes were seen approximately simultaneously for CSF and plasma biomarkers. Overall, plasma biomarkers had smaller dynamic ranges, except for CSF and plasma P-tau which were similar. In conclusion, using state-of-the-art biomarkers, we identified the first changes in A beta, closely followed by soluble tau. Only after A beta PET became abnormal, biomarkers of neuroinflammation, synaptic dysfunction, and neurodegeneration were altered. These findings lend in vivo support of the amyloid cascade hypotheses in humans.
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| 7. |
- Palmqvist, Sebastian, et al.
(författare)
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Performance of Fully Automated Plasma Assays as Screening Tests for Alzheimer Disease-Related beta-Amyloid Status
- 2019
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Ingår i: Jama Neurology. - : American Medical Association (AMA). - 2168-6149. ; 76:9, s. 1060-1069
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Tidskriftsartikel (refereegranskat)abstract
- Key PointsQuestionDo plasma levels of beta -amyloid 42, beta -amyloid 40, and tau detect cerebral beta -amyloid status when measured using fully automated immunoassays? FindingsIn 2 cross-sectional studies, plasma beta -amyloid 42 to beta -amyloid 40 ratio, measured using immunoassay, accurately predicted cerebral beta -amyloid status in all stages of Alzheimer disease in the BioFINDER cohort (n=842) and in an independent validation cohort (n=237). The diagnostic accuracy was further increased by analyzing APOE genotype. MeaningBlood-based beta -amyloid 42 and beta -amyloid 40 ratio together with APOE genotype may be used as prescreening tests in primary care and in clinical Alzheimer disease trials to lower the costs and number of positron emission tomography scans and lumbar punctures. This corss-sectional diagnostic study evaluates the accuracy of fully automated plasma assays in measuring plasma beta -amyloid and tau in patients with and without cognitive impairment in the Swedish BioFINDER study and an independent validation cohort. ImportanceAccurate blood-based biomarkers for Alzheimer disease (AD) might improve the diagnostic accuracy in primary care, referrals to memory clinics, and screenings for AD trials. ObjectiveTo examine the accuracy of plasma beta -amyloid (A beta) and tau measured using fully automated assays together with other blood-based biomarkers to detect cerebral A beta. Design, Setting, and ParticipantsTwo prospective, cross-sectional, multicenter studies. Study participants were consecutively enrolled between July 6, 2009, and February 11, 2015 (cohort 1), and between January 29, 2000, and October 11, 2006 (cohort 2). Data were analyzed in 2018. The first cohort comprised 842 participants (513 cognitively unimpaired [CU], 265 with mild cognitive impairment [MCI], and 64 with AD dementia) from the Swedish BioFINDER study. The validation cohort comprised 237 participants (34 CU, 109 MCI, and 94 AD dementia) from a German biomarker study. Main Outcome and MeasuresThe cerebrospinal fluid (CSF) A beta 42/A beta 40 ratio was used as the reference standard for brain A beta status. Plasma A beta 42, A beta 40 and tau were measured using Elecsys immunoassays (Roche Diagnostics) and examined as predictors of A beta status in logistic regression models in cohort 1 and replicated in cohort 2. Plasma neurofilament light chain (NFL) and heavy chain (NFH) and APOE genotype were also examined in cohort 1. ResultsThe mean (SD) age of the 842 participants in cohort 1 was 72 (5.6) years, with a range of 59 to 88 years, and 446 (52.5%) were female. For the 237 in cohort 2, mean (SD) age was 66 (10) years with a range of 23 to 85 years, and 120 (50.6%) were female. In cohort 1, plasma A beta 42 and A beta 40 predicted A beta status with an area under the receiver operating characteristic curve (AUC) of 0.80 (95% CI, 0.77-0.83). When adding APOE, the AUC increased significantly to 0.85 (95% CI, 0.82-0.88). Slight improvements were seen when adding plasma tau (AUC, 0.86; 95% CI, 0.83-0.88) or tau and NFL (AUC, 0.87; 95% CI, 0.84-0.89) to A beta 42, A beta 40 and APOE. The results were similar in CU and cognitively impaired participants, and in younger and older participants. Applying the plasma A beta 42 and A beta 40 model from cohort 1 in cohort 2 resulted in slightly higher AUC (0.86; 95% CI, 0.81-0.91), but plasma tau did not contribute. Using plasma A beta 42, A beta 40, and APOE in an AD trial screening scenario reduced positron emission tomography costs up to 30% to 50% depending on cutoff. Conclusions and RelevancePlasma A beta 42 and A beta 40 measured using Elecsys immunoassays predict A beta status in all stages of AD with similar accuracy in a validation cohort. Their accuracy can be further increased by analyzing APOE genotype. Potential future applications of these blood tests include prescreening of A beta positivity in clinical AD trials to lower the costs and number of positron emission tomography scans or lumbar punctures.
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