| 1. |
- Arnerić, S. P., et al.
(författare)
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Cerebrospinal fluid biomarkers for Alzheimer's disease: A view of the regulatory science qualification landscape from the coalition against major diseases CSF biomarker team
- 2017
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Ingår i: Journal of Alzheimer's Disease. - 1387-2877 .- 1875-8908. ; 55:1, s. 19-35
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Tidskriftsartikel (refereegranskat)abstract
- Alzheimer's disease (AD) drug development is burdened with the current requirement to conduct large, lengthy, and costly trials to overcome uncertainty in patient progression and effect size on treatment outcome measures. There is an urgent need for the discovery, development, and implementation of novel, objectively measured biomarkers for AD that would aid selection of the appropriate subpopulation of patients in clinical trials, and presumably, improve the likelihood of successfully evaluating innovative treatment options. Amyloid deposition and tau in the brain, which are most commonly assessed either in cerebrospinal fluid (CSF) or by molecular imaging, are consistently and widely accepted. Nonetheless, a clear gap still exists in the accurate identification of subjects that truly have the hallmarks of AD. The Coalition Against Major Diseases (CAMD), one of 12 consortia of the Critical Path Institute (C-Path), aims to streamline drug development for AD and related dementias by advancing regulatory approved drug development tools for clinical trials through precompetitive data sharing and adoption of consensus clinical data standards. This report focuses on the regulatory process for biomarker qualification, briefly comments on how it contrasts with approval or clearance of companion diagnostics, details the qualifications currently available to the field of AD, and highlights the current challenges facing the landscape of CSF biomarkers qualified as hallmarks of AD. Finally, it recommends actions to accelerate regulatory qualification of CSF biomarkers that would, in turn, improve the efficiency of AD therapeutic development. © 2017 - IOS Press and the authors.
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| 2. |
- Manco-Johnson, M. J., et al.
(författare)
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Effect of late prophylaxis in hemophilia on joint status : A randomized trial
- 2017
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Ingår i: Journal of Thrombosis and Haemostasis. - : Elsevier BV. - 1538-7933 .- 1538-7836. ; 15:11, s. 2115-2124
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Tidskriftsartikel (refereegranskat)abstract
- Essentials: High-quality data are lacking on use of prophylaxis in adults with hemophilia and arthropathy. SPINART was a 3-year randomized clinical trial of late/tertiary prophylaxis vs on-demand therapy. Prophylaxis improved function, quality of life, activity and pain but not joint structure by MRI. Prophylaxis improves function but must start before joint bleeding onset to prevent arthropathy. Summary: Background: Limited data exist on the impact of prophylaxis on adults with severe hemophilia A and pre-existing joint disease. Objectives: To describe 3-year bleeding, joint health and structure, health-related quality-of-life (HRQoL) and other outcomes from the open-label, randomized, multinational SPINART study. Patients/Methods: Males aged 12-50 years with severe hemophilia A, ≥ 150 factor VIII exposure days, no inhibitors and no prophylaxis for > 12 consecutive months in the past 5 years were randomized to sucrose-formulated recombinant FVIII prophylaxis or on-demand therapy (OD). Data collected included total and joint bleeding events (BEs), joint structure (magnetic resonance imaging [MRI]), joint health (Colorado Adult Joint Assessment Scale [CAJAS]), HRQoL, pain, healthcare resource utilization (HRU), activity, and treatment satisfaction. Results: Following 3 years of prophylaxis, adults maintained excellent adherence, with a 94% reduction in BEs despite severe pre-existing arthropathy; 35.7% and 76.2% of prophylaxis participants were bleed-free or had fewer than two BEs per year, respectively. As compared with OD, prophylaxis was associated with improved CAJAS scores (least squares [LS] mean, - 0.31 [n = 42] versus + 0.63 [n = 42]) and HAEMO-QoL-A scores (LS mean, + 3.98 [n = 41] versus - 6.00 [n = 42]), less chronic pain (50% decrease), and approximately two-fold less HRU; activity, Euro QoL-5D-3L (EQ-5D-3L) scores and satisfaction scores also favored prophylaxis. However, MRI score changes were not different for prophylaxis versus OD (LS mean, + 0.79 [n = 41] versus + 0.96 [n = 38]). Conclusions: Over a period of 3 years, prophylaxis versus OD in adults with severe hemophilia A and arthropathy led to decreased bleeding, pain, and HRU, better joint health, activity, satisfaction, and HRQoL, but no reduction in structural arthropathy progression, suggesting that pre-existing joint arthropathy may be irreversible.
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| 3. |
- Hong, W., et al.
(författare)
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SPINART study : validation of the extended magnetic resonance imaging scale for evaluation of joint status in adult patients with severe haemophilia A using baseline data
- 2016
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Ingår i: Haemophilia. - : Wiley. - 1351-8216 .- 1365-2516. ; 22:6, s. 519-526
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Most previous joint imaging scales for haemophilia have focused on earlier disease stages observed in younger patients. Aim: We sought to demonstrate that the 45-item extended magnetic resonance imaging (eMRI) scale is a valid instrument for measuring joint status in adults with severe haemophilia A. Methods: Six scale categories (effusion/haemarthrosis, synovial hypertrophy, hemosiderin, erosion, subchondral cysts and cartilage loss) in two domains (soft tissue [range = 0–9] and osteochondral [range = 0–36]) were evaluated for each joint. eMRI scores were derived using baseline data from a randomized, controlled, parallel-group clinical trial (SPINART). Quantitative analysis of linearity included assessments of the relationship between scores derived from the eMRI scale vs. the 17-point International Prophylaxis Study Group (IPSG) MRI scale and Colorado Adult Joint Assessment Scale (CAJAS). Results: Patient eMRI scores correlated with age (r = 0.58), consistent with the expectation of arthropathy progression and more severe joint changes in older patients. eMRI scores demonstrated excellent between-reader agreement for overall patient score (intraclass correlation coefficient [ICC] = 0.88) and outstanding agreement for knee evaluations (ICC = 0.95). There was a strong linear relationship of the eMRI score with the CAJAS (r = 0.7). Adding individual bone evaluations for each joint increased the sensitivity of the instrument to detect change at low scores. There was minimal ceiling effect (5% maximum scores for all evaluated joints) compared with the IPSG MRI scale (20%). Internal reliability was good (overall Cronbach's alpha = 0.75). Conclusions: Overall, the eMRI scale represents a valid and reliable measure of joint status in adolescents and adults with severe haemophilia A.
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| 4. |
- Zicha, S., et al.
(författare)
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Comparative analytical performance of multiple plasma A beta 42 and A beta 40 assays and their ability to predict positron emission tomography amyloid positivity
- 2022
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Ingår i: Alzheimers & Dementia. - : Wiley. - 1552-5260 .- 1552-5279.
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Tidskriftsartikel (refereegranskat)abstract
- Introduction This report details the approach taken to providing a dataset allowing for analyses on the performance of recently developed assays of amyloid beta (A beta) peptides in plasma and the extent to which they improve the prediction of amyloid positivity. Methods Alzheimer's Disease Neuroimaging Initiative plasma samples with corresponding amyloid positron emission tomography (PET) data were run on six plasma A beta assays. Statistical tests were performed to determine whether the plasma A beta measures significantly improved the area under the receiver operating characteristic curve for predicting amyloid PET status compared to age and apolipoprotein E (APOE) genotype. Results The age and APOE genotype model predicted amyloid status with an area under the curve (AUC) of 0.75. Three assays improved AUCs to 0.81, 0.81, and 0.84 (P < .05, uncorrected for multiple comparisons). Discussion Measurement of A beta in plasma contributes to addressing the amyloid component of the ATN (amyloid/tau/neurodegeneration) framework and could be a first step before or in place of a PET or cerebrospinal fluid screening study. Highlights The Foundation of the National Institutes of Health Biomarkers Consortium evaluated six plasma amyloid beta (A beta) assays using Alzheimer's Disease Neuroimaging Initiative samples. Three assays improved prediction of amyloid status over age and apolipoprotein E (APOE) genotype. Plasma A beta 42/40 predicted amyloid positron emission tomography status better than A beta 42 or A beta 40 alone.
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