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1.
Artigo em Inglês | MEDLINE | ID: mdl-31364818

RESUMO

BACKGROUND: The pathophysiology of multiple sclerosis disease progression remains undetermined. The aim of this study was to identify differences in plasma proteome during different stages of MS disease progression. METHODS: We used a multiplex aptamer proteomics platform (Somalogic) for sensitive detection of 1129 proteins in plasma. MS patients were selected and categorized based on baseline and a 4-year follow-up EDSS (delta EDSS) scores; relapse-onset (RO) slow progression (n = 31), RO with rapid progression (n = 29), primary progressive (n = 30), and healthy controls (n = 20). The relation of baseline plasma protein levels with delta EDSS and different MRI progression parameters were assessed using linear regression models. RESULTS: Regression analyses of plasma proteins with delta EDSS showed six significant associations. Strong associations were found for the proteins LGLAS8 (P = 7.64 × 10-5 , q = 0.06), CCL3 (P = 0.0001, q = 0.06), and RGMA (P = 0.0005, q = 0.09). In addition, associations of plasma proteins were found with percentage brain volume for C3 (P = 2,08 × 10-9 , q = 1,70 × 10-6 ), FGF9 (P = 3,42 × 10-9 , q = 1,70 × 10-6 ), and EHMT2 (P = 0.0007, q = 0.01). Most of the significant markers were associated with cell-cell and cell-extracellular matrix adhesion, immune system communication, immune system activation, and complement pathways. CONCLUSIONS: Our results revealed eight novel biomarkers related to clinical and radiological progression in MS. These results indicate that changes in immune system, complement pathway and ECM remodeling proteins contribute to MS progression and may therefore be further explored for use in prognosis of MS.

2.
Hum Brain Mapp ; 40(14): 4091-4104, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31206931

RESUMO

Neurodegenerative disorders, such as Alzheimer's disease (AD) and progressive forms of multiple sclerosis (MS), can affect the brainstem and are associated with atrophy that can be visualized by MRI. Anatomically accurate, large-scale assessments of brainstem atrophy are challenging due to lack of automated, accurate segmentation methods. We present a novel method for brainstem volumetry using a fully-automated segmentation approach based on multi-dimensional gated recurrent units (MD-GRU), a deep learning based semantic segmentation approach employing a convolutional adaptation of gated recurrent units. The neural network was trained on 67 3D-high resolution T1-weighted MRI scans from MS patients and healthy controls (HC) and refined using segmentations of 20 independent MS patients' scans. Reproducibility was assessed in MR test-retest experiments in 33 HC. Accuracy and robustness were examined by Dice scores comparing MD-GRU to FreeSurfer and manual brainstem segmentations in independent MS and AD datasets. The mean %-change/SD between test-retest brainstem volumes were 0.45%/0.005 (MD-GRU), 0.95%/0.009 (FreeSurfer), 0.86%/0.007 (manually edited segmentations). Comparing MD-GRU to manually edited segmentations the mean Dice scores/SD were: 0.97/0.005 (brainstem), 0.95/0.013 (mesencephalon), 0.98/0.006 (pons), 0.95/0.015 (medulla oblongata). Compared to the manual gold standard, MD-GRU brainstem segmentations were more accurate than FreeSurfer segmentations (p < .001). In the multi-centric acquired AD data, the mean Dice score/SD for the MD-GRU-manual segmentation comparison was 0.97/0.006. The fully automated brainstem segmentation method MD-GRU provides accurate, highly reproducible, and robust segmentations in HC and patients with MS and AD in 200 s/scan on an Nvidia GeForce GTX 1080 GPU and shows potential for application in large and longitudinal datasets.

3.
J Neuroinflammation ; 15(1): 255, 2018 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-30185189

RESUMO

BACKGROUND: We compared the magnetic resonance imaging (MRI) features between Japanese and Caucasian patients with multiple sclerosis (MS), and identified the relationships between MRI features and disability. METHODS: From the baseline data of phase II fingolimod trials, 95 Japanese and 246 Caucasian relapsing-remitting MS patients were enrolled. The number, volume, and distribution of brain MRI lesions were evaluated using T2-weighted (T2W) images. Cross-sectional total normalized brain volume (NBV), normalized cortical gray matter volume, normalized deep gray matter volume (NDGMV), normalized white matter volume (NWMV), and normalized thalamic volume were measured. RESULTS: Japanese patients had significantly lower Expanded Disability Status Scale (EDSS) scores than Caucasian patients (mean 2.0 vs. 2.3, p = 0.008), despite a similar disease duration. Japanese patients showed a trend towards fewer T2W-lesions (median 50 vs. 65, p = 0.08) and significantly lower frequencies of cerebellar and parietal lobe lesions (p = 0.02 for both) than Caucasian patients. There were no differences in T2W-lesion volume between races, whereas Japanese patients had a significantly larger T2W-lesion volume per lesion compared with Caucasian patients (median 140 mm3 vs. 85 mm3, p < 0.0001). T2W-lesion volumes were positively correlated with EDSS scores in Japanese patients (p < 0.0001). In both races, NBV, normalized cortical gray matter volume, NDGMV, and thalamic volume were negatively correlated with disease duration and EDSS scores (p < 0.01 for all). NWMV was negatively correlated with disease duration and EDSS scores only in Caucasian patients (p = 0.03 and p = 0.004, respectively). NBV, NDGMV, NWMV, and thalamic volume were consistently smaller in Japanese compared with Caucasian patients throughout the entire examined disease duration (p = 0.046, p = 0.01, p = 0.005, and p = 0.04, respectively). Japanese patients had a significantly faster reduction in NDGMV (p = 0.001), particularly for thalamic volume (p = 0.001), with disease duration compared with Caucasian patients. CONCLUSIONS: Gray matter atrophy is a common denominator for disability in Japanese and Caucasian patients. Additional contributory factors for disability include T2W-lesion volume in Japanese patients and white matter atrophy in Caucasian patients. Less frequent parietal and cerebellar involvement with fewer T2W-lesions may underlie milder disability in Japanese patients.

4.
Brain Imaging Behav ; 2018 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-30155789

RESUMO

Neuroanatomical pattern classification using support vector machines (SVMs) has shown promising results in classifying Multiple Sclerosis (MS) patients based on individual structural magnetic resonance images (MRI). To determine whether pattern classification using SVMs facilitates predicting conversion to clinically definite multiple sclerosis (CDMS) from clinically isolated syndrome (CIS). We used baseline MRI data from 364 patients with CIS, randomised to interferon beta-1b or placebo. Non-linear SVMs and 10-fold cross-validation were applied to predict converters/non-converters (175/189) at two years follow-up based on clinical and demographic data, lesion-specific quantitative geometric features and grey-matter-to-whole-brain volume ratios. We applied linear SVM analysis and leave-one-out cross-validation to subgroups of converters (n = 25) and non-converters (n = 44) based on cortical grey matter segmentations. Highest prediction accuracies of 70.4% (p = 8e-5) were reached with a combination of lesion-specific geometric (image-based) and demographic/clinical features. Cortical grey matter was informative for the placebo group (acc.: 64.6%, p = 0.002) but not for the interferon group. Classification based on demographic/clinical covariates only resulted in an accuracy of 56% (p = 0.05). Overall, lesion geometry was more informative in the interferon group, EDSS and sex were more important for the placebo cohort. Alongside standard demographic and clinical measures, both lesion geometry and grey matter based information can aid prediction of conversion to CDMS.

5.
Brain ; 2018 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-29860296

RESUMO

Neuro-axonal injury is a key factor in the development of permanent disability in multiple sclerosis. Neurofilament light chain in peripheral blood has recently emerged as a biofluid marker reflecting neuro-axonal damage in this disease. We aimed at comparing serum neurofilament light chain levels in multiple sclerosis and healthy controls, to determine their association with measures of disease activity and their ability to predict future clinical worsening as well as brain and spinal cord volume loss. Neurofilament light chain was measured by single molecule array assay in 2183 serum samples collected as part of an ongoing cohort study from 259 patients with multiple sclerosis (189 relapsing and 70 progressive) and 259 healthy control subjects. Clinical assessment, serum sampling and MRI were done annually; median follow-up time was 6.5 years. Brain volumes were quantified by structural image evaluation using normalization of atrophy, and structural image evaluation using normalization of atrophy, cross-sectional, cervical spinal cord volumes using spinal cord image analyser (cordial). Results were analysed using ordinary linear regression models and generalized estimating equation modelling. Serum neurofilament light chain was higher in patients with a clinically isolated syndrome or relapsing remitting multiple sclerosis as well as in patients with secondary or primary progressive multiple sclerosis than in healthy controls (age adjusted P < 0.001 for both). Serum neurofilament light chain above the 90th percentile of healthy controls values was an independent predictor of Expanded Disability Status Scale worsening in the subsequent year (P < 0.001). The probability of Expanded Disability Status Scale worsening gradually increased by higher serum neurofilament light chain percentile category. Contrast enhancing and new/enlarging lesions were independently associated with increased serum neurofilament light chain (17.8% and 4.9% increase per lesion respectively; P < 0.001). The higher the serum neurofilament light chain percentile level, the more pronounced was future brain and cervical spinal volume loss: serum neurofilament light chain above the 97.5th percentile was associated with an additional average loss in brain volume of 1.5% (P < 0.001) and spinal cord volume of 2.5% over 5 years (P = 0.009). Serum neurofilament light chain correlated with concurrent and future clinical and MRI measures of disease activity and severity. High serum neurofilament light chain levels were associated with both brain and spinal cord volume loss. Neurofilament light chain levels are a real-time, easy to measure marker of neuro-axonal injury that is conceptually more comprehensive than brain MRI.

6.
Neurology ; 91(3): e249-e257, 2018 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-29925550

RESUMO

OBJECTIVE: In the work-up of patients presenting with a clinically isolated syndrome (CIS), 3T MRI might offer a higher lesion detection than 1.5T, but it remains unclear whether this affects the fulfilment of the diagnostic criteria for multiple sclerosis (MS). METHODS: We recruited 66 patients with CIS within 6 months from symptom onset and 26 healthy controls in 6 MS centers. All participants underwent 1.5T and 3T brain and spinal cord MRI at baseline according to local optimized protocols and the MAGNIMS guidelines. Patients who had not converted to MS during follow-up received repeat brain MRI at 3-6 months and 12-15 months. The number of lesions per anatomical region was scored by 3 raters in consensus. Criteria for dissemination in space (DIS) and dissemination in time (DIT) were determined according to the 2017 revisions of the McDonald criteria. RESULTS: Three-Tesla MRI detected 15% more T2 brain lesions compared to 1.5T (p < 0.001), which was driven by an increase in baseline detection of periventricular (12%, p = 0.015), (juxta)cortical (21%, p = 0.005), and deep white matter lesions (21%, p < 0.001). The detection rate of spinal cord lesions and gadolinium-enhancing lesions did not differ between field strengths. Three-Tesla MRI did not lead to a higher number of patients fulfilling the criteria for DIS or DIT, or subsequent diagnosis of MS, at any of the 3 time points. CONCLUSION: Scanning at 3T does not influence the diagnosis of MS according to McDonald diagnostic criteria.

7.
Neurology ; 91(4): e349-e358, 2018 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-29950437

RESUMO

OBJECTIVE: Cross-sectional studies have shown that spinal cord volume (SCV) loss is related to disease severity in multiple sclerosis (MS). However, long-term data are lacking. Our aim was to evaluate SCV loss as a biomarker of disease progression in comparison to other MRI measurements in a large cohort of patients with relapse-onset MS with 6-year follow-up. METHODS: The upper cervical SCV, the total brain volume, and the brain T2 lesion volume were measured annually in 231 patients with MS (180 relapsing-remitting [RRMS] and 51 secondary progressive [SPMS]) over 6 years on 3-dimensional, T1-weighted, magnetization-prepared rapid-acquisition gradient echo images. Expanded Disability Status Scale (EDSS) score and relapses were recorded at every follow-up. RESULTS: Patients with SPMS had lower baseline SCV (p < 0.01) but no accelerated SCV loss compared to those with RRMS. Clinical relapses were found to predict SCV loss over time (p < 0.05) in RRMS. Furthermore, SCV loss, but not total brain volume and T2 lesion volume, was a strong predictor of EDSS score worsening over time (p < 0.05). The mean annual rate of SCV loss was the strongest MRI predictor for the mean annual EDSS score change of both RRMS and SPMS separately, while correlating stronger in SPMS. Every 1% increase of the annual SCV loss rate was associated with an extra 28% risk increase of disease progression in the following year in both groups. CONCLUSION: SCV loss over time relates to the number of clinical relapses in RRMS, but overall does not differ between RRMS and SPMS. SCV proved to be a strong predictor of physical disability and disease progression, indicating that SCV may be a suitable marker for monitoring disease activity and severity.

8.
Mult Scler ; : 1352458518775006, 2018 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-29781383

RESUMO

BACKGROUND: Little is known on longer term changes of spinal cord volume (SCV) in primary progressive multiple sclerosis (PPMS). OBJECTIVE: Longitudinal evaluation of SCV loss in PPMS and its correlation to clinical outcomes, compared to relapse-onset multiple sclerosis (MS) subtypes. METHODS: A total of 60 MS age-, sex- and disease duration-matched patients (12 PPMS, each 24 relapsing-remitting (RRMS) and secondary progressive MS (SPMS)) were analysed annually over 6 years of follow-up. The upper cervical SCV was measured on 3D T1-weighted magnetization-prepared rapid gradient-echo (MPRAGE) images using a semi-automatic software (CORDIAL), along with the total brain volume (TBV), brain T2 lesion volume (T2LV) and Expanded Disability Status Scale (EDSS). RESULTS: PPMS showed faster SCV loss over time than RRMS ( p < 0.01) and by trend ( p = 0.066) compared with SPMS. In contrast to relapse-onset MS, in PPMS SCV loss progressed independent of TBV and T2LV changes. Moreover, in PPMS, SCV was the only magnetic resonance imaging (MRI) measurement associated with EDSS increase over time ( p < 0.01), as opposed to RRMS and SPMS. CONCLUSION: SCV loss is a strong predictor of clinical outcomes in PPMS and has shown to be faster and independent of brain MRI metrics compared to relapse-onset MS.

9.
Eur Radiol ; 28(11): 4488-4495, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29713776

RESUMO

OBJECTIVE: To validate the precision and accuracy of the semi-automated cord image analyser (Cordial) for lumbar spinal cord (SC) volumetry in 3D T1w MRI data of healthy controls (HC). MATERIALS AND METHODS: 40 3D T1w images of 10 HC (w/m: 6/4; age range: 18-41 years) were acquired at one 3T-scanner in two MRI sessions (time interval 14.9±6.1 days). Each subject was scanned twice per session, allowing determination of test-retest reliability both in back-to-back (intra-session) and scan-rescan images (inter-session). Cordial was applied for lumbar cord segmentation twice per image by two raters, allowing for assessment of intra- and inter-rater reliability, and compared to a manual gold standard. RESULTS: While manually segmented volumes were larger (mean: 2028±245 mm3 vs. Cordial: 1636±300 mm3, p<0.001), accuracy assessments between manually and semi-automatically segmented images showed a mean Dice-coefficient of 0.88±0.05. Calculation of within-subject coefficients of variation (COV) demonstrated high intra-session (1.22-1.86%), inter-session (1.26-1.84%), as well as intra-rater (1.73-1.83%) reproducibility. No significant difference was shown between intra- and inter-session reproducibility or between intra-rater reliabilities. Although inter-rater reproducibility (COV: 2.87%) was slightly lower compared to all other reproducibility measures, between rater consistency was very strong (intraclass correlation coefficient: 0.974). CONCLUSION: While under-estimating the lumbar SCV, Cordial still provides excellent inter- and intra-session reproducibility showing high potential for application in longitudinal trials. KEY POINTS: • Lumbar spinal cord segmentation using the semi-automated cord image analyser (Cordial) is feasible. • Lumbar spinal cord is 40-mm cord segment 60 mm above conus medullaris. • Cordial provides excellent inter- and intra-session reproducibility in lumbar spinal cord region. • Cordial shows high potential for application in longitudinal trials.

10.
J Thromb Thrombolysis ; 45(3): 432-439, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29349545

RESUMO

In patients at high risk for bleeding undergoing percutaneous coronary intervention (PCI) the use of bare-metal-stent (BMS) is considered an option that allows discontinuation of clopidogrel after 4 weeks. We sought to investigate the risk of early discontinuation of clopidogrel in patients with BMS as compared with a 6-month course of clopidogrel after DES in patients with or without high on-treatment platelet reactivity (HTPR). In 765 consecutive patients undergoing PCI after loading with clopidogrel 600 mg, HTPR was tested by optical aggregometry and defined as residual platelet reactivity > 14%. On top of aspirin 100 mg, patients received clopidogrel 75 mg for 4 weeks after BMS or 6 months after DES. The primary endpoint was all-cause mortality or myocardial infarction (MI) during 1 year. The 1-year incidence of death or MI was 3.5% with BMS (n = 484), 0.9% with DES and no HTPR (n = 211), and 7.1% with DES and HTPR (n = 70; p = 0.03). Landmark analyses for the first 6 months demonstrated that the risk of patients receiving BMS was similar as in patients receiving a DES with HTPR during this period (2.3 vs. 2.9%) but lowest in patients receiving a DES without HTPR (0.5%). The incidence of bleeding was similar in all three groups. These findings did not change after propensity score adjustment for stent type. After discontinuation of clopidogrel at 1 month, patients treated with BMS are at higher risk for death or MI than patients treated with a DES and sufficiently responding to clopidogrel planned for 6 months.ClinicalTrials.gov number NCT00457236.


Assuntos
Stents Farmacológicos , Stents , Ticlopidina/análogos & derivados , Idoso , Clopidogrel , Stents Farmacológicos/estatística & dados numéricos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mortalidade , Infarto do Miocárdio , Inibidores da Agregação de Plaquetas/uso terapêutico , Pontuação de Propensão , Stents/estatística & dados numéricos , Ticlopidina/administração & dosagem , Ticlopidina/uso terapêutico , Fatores de Tempo
11.
Mult Scler ; : 1352458517751647, 2018 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-29327668

RESUMO

BACKGROUND: Compared to 1.5 T, 3 T magnetic resonance imaging (MRI) increases signal-to-noise ratio leading to improved image quality. However, its clinical relevance in clinically isolated syndrome suggestive of multiple sclerosis remains uncertain. OBJECTIVES: The purpose of this study was to investigate how 3 T MRI affects the agreement between raters on lesion detection and diagnosis. METHODS: We selected 30 patients and 10 healthy controls from our ongoing prospective multicentre cohort. All subjects received baseline 1.5 and 3 T brain and spinal cord MRI. Patients also received follow-up brain MRI at 3-6 months. Four experienced neuroradiologists and four less-experienced raters scored the number of lesions per anatomical region and determined dissemination in space and time (McDonald 2010). RESULTS: In controls, the mean number of lesions per rater was 0.16 at 1.5 T and 0.38 at 3 T ( p = 0.005). For patients, this was 4.18 and 4.40, respectively ( p = 0.657). Inter-rater agreement on involvement per anatomical region and dissemination in space and time was moderate to good for both field strengths. 3 T slightly improved agreement between experienced raters, but slightly decreased agreement between less-experienced raters. CONCLUSION: Overall, the interobserver agreement was moderate to good. 3 T appears to improve the reading for experienced readers, underlining the benefit of additional training.

12.
Eur Neurol ; 80(3-4): 207-214, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30605898

RESUMO

BACKGROUND: Structural Image Evaluation using Normalization of Atrophy (SIENA) is used to measure brain atrophy in multiple sclerosis (MS). However, brain extraction is prone to artefacts in the upper and lower parts of the brain. To overcome these shortcomings, some pivotal MS trials used a central slab instead of the whole brain as input for SIENA. The aim of this study was to compare the internal consistency and statistical dispersion of atrophy measures, associations with clinical outcomes and required sample sizes in clinical trials between these two approaches. METHODS: Brain volume change was assessed using SIENA in 119 MS patients with 5-years follow-up on 3D T1-weighted Magnetization Prepared Rapid Gradient Echo datasets using the whole brain or a central slab ranging from -10 to +60 mm Montreal Neurological Institute atlas coordinates. The statistical analysis included the quartile coefficient of dispersion, partial correlations with clinical outcomes and sample size calculations. Clinical outcome measures comprised the Expanded Disability Status Scale, MS Functional Composite and Symbol Digit Modalities Test. RESULTS: Annualized brain atrophy rates were higher using central slab than whole brain as input for SIENA (-0.51 ± 0.49 vs. -0.37 ± 0.39% per year, p < 0.001). Central and whole brain volume change showed comparable statistical dispersion and similarly correlated with clinical outcomes at 5-years follow-up. Sample size calculations estimated 14% fewer patients required to detect a given treatment effect when using the central slab instead of the whole brain option in SIENA. CONCLUSION: Central slab and whole brain SIENA produced comparable statistical dispersion with similar associations to clinical outcomes.


Assuntos
Encéfalo/patologia , Interpretação de Imagem Assistida por Computador/métodos , Esclerose Múltipla/patologia , Adulto , Atrofia/patologia , Feminino , Humanos , Imagem por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade
13.
Thromb Haemost ; 117(8): 1644-1650, 2017 07 26.
Artigo em Inglês | MEDLINE | ID: mdl-28382368

RESUMO

It is unknown whether the known association of high on-treatment platelet reactivity (HTPR) with worse clinical outcome in patients on clopidogrel following coronary stent implantation persists after planned discontinuation of clopidogrel. This study investigated the association of HTPR with major ischaemic events after planned discontinuation of clopidogrel. Consecutive patients undergoing elective coronary stent implantation after loading with clopidogrel 600 mg were followed for up to seven years (n=765). Platelet reactivity was tested on day 1 after coronary intervention. Clopidogrel was continued for six months after implantation of drug-eluting stents and for one month if only bare-metal stents were used. The combined primary endpoint was death of any cause or non-fatal myocardial infarction (MACE). HTPR was found in 217 of 765 patients (28 %). During a median follow-up of 5.7 years, the primary endpoint occurred in 145 subjects after planned discontinuation of clopidogrel. Patients with HTPR showed a higher incidence of MACE after discontinuation of clopidogrel. There was a significant interaction of HTPR and time following discontinuation of clopidogrel beyond one year (p for interaction 0.08). Landmark analyses confirmed that the association of HTPR and MACE was only significant within the first year (HR: 2.93, 95 %-CI 1.13-7.60, p=0.03), but not beyond the first year following discontinuation of clopidogrel (HR: 1.19, 95 %-CI 0.82-1.72, p=0.37). In conclusion, patients with HTPR persist to be at high risk for death or myocardial infarction even following planned discontinuation of clopidogrel. However, this association was only significant for the first year following discontinuation of clopidogrel.


Assuntos
Doença da Artéria Coronariana/terapia , Intervenção Coronária Percutânea , Ativação Plaquetária/efeitos dos fármacos , Inibidores da Agregação de Plaquetas/administração & dosagem , Ticlopidina/análogos & derivados , Idoso , Clopidogrel , Angiografia Coronária , Doença da Artéria Coronariana/diagnóstico por imagem , Doença da Artéria Coronariana/mortalidade , Esquema de Medicação , Resistência a Medicamentos , Feminino , Alemanha , Humanos , Estimativa de Kaplan-Meier , Masculino , Infarto do Miocárdio/etiologia , Infarto do Miocárdio/mortalidade , Intervenção Coronária Percutânea/efeitos adversos , Intervenção Coronária Percutânea/instrumentação , Intervenção Coronária Percutânea/mortalidade , Inibidores da Agregação de Plaquetas/efeitos adversos , Testes de Função Plaquetária , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Stents , Ticlopidina/administração & dosagem , Ticlopidina/efeitos adversos , Fatores de Tempo , Resultado do Tratamento
14.
JACC Cardiovasc Interv ; 10(2): 121-129, 2017 01 23.
Artigo em Inglês | MEDLINE | ID: mdl-28104204

RESUMO

OBJECTIVES: This randomized trial tested whether early loading with prasugrel can provide sufficient platelet inhibition even when given at the start of a 2-h infusion of cangrelor. BACKGROUND: Effective platelet inhibition with intravenous cangrelor reduces the risk of ischemic complications during percutaneous coronary intervention (PCI). Transitioning to oral therapy with clopidogrel or prasugrel is only recommended after discontinuation of cangrelor due to drug interactions. Given the long half-life of prasugrel, this drug could achieve effective platelet inhibition even when given early under cangrelor and thereby prevent a transient gap in platelet inhibition. METHODS: This trial randomized 110 P2Y12-receptor blocker-naive patients undergoing PCI with use of cangrelor to loading with prasugrel 60 mg or ticagrelor 180 mg at the start of cangrelor (n = 45 each) or loading with clopidogrel 600 mg after discontinuation of cangrelor (n = 20). The primary endpoint was the proportion of patients without high on-treatment platelet reactivity 1 h after stopping cangrelor. RESULTS: The 3 groups were well balanced with respect to clinical parameters. One hour following discontinuation of cangrelor, the primary endpoint was seen in 65.0% of patients on clopidogrel versus 95.6% with ticagrelor and 93.3% with prasugrel (p for superiority of prasugrel vs. clopidogrel = 0.003; p of prasugrel vs. ticagrelor = 0.65). The 30-day incidence of ischemic and bleeding events was similar in all groups. CONCLUSIONS: Prasugrel 60 mg given at the start of a 2-h infusion of cangrelor can provide a sufficient platelet inhibition post-cangrelor. This approach prevents the transient gap in platelet inhibition seen with oral loading after discontinuation of cangrelor. (Impact of Extent of Clopidogrel-Induced Platelet Inhibition during Elective Stent Implantation on Clinical Event Rate - Advanced Loading Strategies [ExcelsiorLOAD2]; DRKS00009739).


Assuntos
Monofosfato de Adenosina/análogos & derivados , Adenosina/análogos & derivados , Plaquetas/efeitos dos fármacos , Doença das Coronárias/terapia , Substituição de Medicamentos , Intervenção Coronária Percutânea , Inibidores da Agregação de Plaquetas/administração & dosagem , Cloridrato de Prasugrel/administração & dosagem , Antagonistas do Receptor Purinérgico P2Y/administração & dosagem , Ticlopidina/análogos & derivados , Adenosina/administração & dosagem , Adenosina/efeitos adversos , Monofosfato de Adenosina/administração & dosagem , Monofosfato de Adenosina/efeitos adversos , Administração Oral , Idoso , Plaquetas/metabolismo , Clopidogrel , Doença das Coronárias/sangue , Doença das Coronárias/diagnóstico por imagem , Feminino , Alemanha , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Intervenção Coronária Percutânea/efeitos adversos , Intervenção Coronária Percutânea/instrumentação , Agregação Plaquetária/efeitos dos fármacos , Inibidores da Agregação de Plaquetas/efeitos adversos , Testes de Função Plaquetária , Cloridrato de Prasugrel/efeitos adversos , Estudos Prospectivos , Antagonistas do Receptor Purinérgico P2Y/efeitos adversos , Receptores Purinérgicos P2Y12/sangue , Receptores Purinérgicos P2Y12/efeitos dos fármacos , Stents , Ticagrelor , Ticlopidina/administração & dosagem , Ticlopidina/efeitos adversos , Fatores de Tempo , Resultado do Tratamento
15.
Thromb Haemost ; 116(5): 941-948, 2016 10 28.
Artigo em Inglês | MEDLINE | ID: mdl-27487961

RESUMO

Reticulated platelets are associated with impaired antiplatelet response to thienopyridines. It is uncertain whether this interaction is caused by a decreased drug exposure due to high platelet turnover reflected by elevated levels of reticulated platelets or by intrinsic properties of reticulated platelets. This study sought to investigate if the impact of reticulated platelets on early antiplatelet response to thienopyridines is mainly caused by platelet turnover as previously suggested. Elective patients undergoing coronary intervention were randomised to loading with clopidogrel 600 mg or prasugrel 60 mg (n=200). Adenosine diphosphate (ADP)-induced platelet reactivity was determined by impedance aggregometry before, at 30, 60, 90, and 120 minutes and at day 1 after loading. Immature platelet count was assessed as marker of reticulated platelets by flow cytometry. Platelet reactivity increased with rising levels of immature platelet count in both groups. This effect was more distinctive in patients on clopidogrel as compared to patients on prasugrel. Overall, immature platelet count correlated well with on-treatment platelet reactivity at all time-points (p < 0.001). These correlations did not change over time in the entire cohort as well as in patients treated with clopidogrel or prasugrel indicating an effect independent of platelet turnover (comparison of correlations 120 minutes/day 1: p = 0.64). In conclusion, the association of immature platelet count with impaired antiplatelet response to thienopyridines is similar early and late after loading. This finding suggests as main underlying mechanism another effect of reticulated platelets on thienopyridines than platelet turnover.


Assuntos
Plaquetas/citologia , Plaquetas/efeitos dos fármacos , Cloridrato de Prasugrel/farmacologia , Tienopiridinas/farmacologia , Ticlopidina/farmacologia , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Inibidores da Agregação de Plaquetas , Contagem de Plaquetas
16.
J Am Coll Cardiol ; 68(3): 286-293, 2016 07 19.
Artigo em Inglês | MEDLINE | ID: mdl-27417007

RESUMO

BACKGROUND: Previous data suggest that reticulated platelets significantly affect antiplatelet response to thienopyridines. It is unknown whether parameters describing reticulated platelets can predict antiplatelet response to thienopyridines. OBJECTIVES: The authors sought to determine the extent to which parameters describing reticulated platelets can predict antiplatelet response to thienopyridine loading compared with established predictors. METHODS: This study randomized 300 patients undergoing elective coronary stenting to loading with clopidogrel 600 mg, prasugrel 30 mg, or prasugrel 60 mg. Adenosine diphosphate (ADP)-induced platelet reactivity was assessed by impedance aggregometry before loading (intrinsic platelet reactivity) and again on day 1 after loading. Multiple parameters of reticulated platelets were assessed by automated whole blood flow cytometry: absolute immature platelet count (IPC), immature platelet fraction, and highly fluorescent immature platelet fraction. RESULTS: Each parameter of reticulated platelets correlated significantly with ADP-induced platelet reactivity (p < 0.01 for all 3 parameters). In a multivariable model including all 3 parameters, only IPC remained a significant predictor of platelet reactivity (p < 0.001). In models adjusting each of the 3 parameters for known predictors of on-treatment platelet reactivity including cytochrome P450 2C19 (CYP2C19) polymorphisms, age, body mass index, diabetes, and intrinsic platelet reactivity, only IPC prevailed as an independent predictor (p = 0.001). In this model, IPC was the strongest predictor of on-treatment platelet reactivity followed by intrinsic platelet reactivity. CONCLUSIONS: IPC is the strongest independent platelet count-derived predictor of antiplatelet response to thienopyridine treatment. Given its easy availability, together with its even stronger association with on-treatment platelet reactivity compared with known predictors, including the CYP2C19*2 polymorphism, IPC may become the preferred predictor of antiplatelet response to thienopyridine treatment. (Impact of Extent of Clopidogrel-Induced Platelet Inhibition During Elective Stent Implantation on Clinical Event Rate-Advanced Loading Strategies [ExcelsiorLOAD]; DRKS00006102).


Assuntos
Plaquetas/efeitos dos fármacos , Doença da Artéria Coronariana/sangue , Agregação Plaquetária/efeitos dos fármacos , Piridinas/administração & dosagem , Idoso , Doença da Artéria Coronariana/tratamento farmacológico , Doença da Artéria Coronariana/cirurgia , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Intervenção Coronária Percutânea , Contagem de Plaquetas , Stents , Resultado do Tratamento
17.
EuroIntervention ; 12(3): 329-36, 2016 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-27320427

RESUMO

AIMS: Elevated levels of high-sensitivity troponin are seen in a significant proportion of stable patients undergoing elective coronary assessment. Multiple variables have been associated with troponin levels. The present analysis sought to identify variables independently associated with elevations of troponin and their relative strength of association with this biomarker. METHODS AND RESULTS: Stable patients undergoing elective coronary angiography and echocardiographic assessment were enrolled. High-sensitivity troponin T (hsTnT) was determined before any diagnostic procedures. Multivariable linear regression models including angiographic and echocardiographic parameters were used to identify independent predictors of levels of troponin and to determine their relative contribution to levels of troponin. Out of 2,046 patients, 15% presented with levels of troponin above the upper reference limit of normal. In a combined analysis, gender followed by renal function, age, left ventricular ejection fraction, diabetes, and left ventricular mass showed the strongest association with levels of troponin. Coronary obstruction was also an independent predictor, but strength of association weakened following adjustment. CONCLUSIONS: Up to 15% of patients undergoing coronary assessment outside the setting of acute coronary syndromes present with elevated levels of cardiac troponin. These changes are independently associated with multiple clinical, laboratory, and imaging variables.


Assuntos
Angiografia Coronária , Doença da Artéria Coronariana/diagnóstico , Troponina/sangue , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/análise , Angiografia Coronária/métodos , Doença da Artéria Coronariana/terapia , Ecocardiografia/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Fatores de Risco
18.
J Neurol ; 263(7): 1364-74, 2016 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-27159989

RESUMO

Spinal cord (SC) atrophy is an important contributor to the development of disability in many neurological disorders including multiple sclerosis (MS). To assess the spinal cord atrophy in clinical trials and clinical practice, largely automated methods are needed due to the sheer amount of data. Moreover, using these methods in longitudinal trials requires them to deliver highly reliable measurements, enabling comparisons of multiple data sets of the same subject over time. We present a method for SC volumetry using 3D MRI data providing volume measurements for SC sections of fixed length and location. The segmentation combines a continuous max flow approach with SC surface reconstruction that locates the SC boundary based on image voxel intensities. Two cutting planes perpendicular to the SC centerline are determined based on predefined distances to an anatomical landmark, and the cervical SC volume (CSCV) is then calculated in-between these boundaries. The development of the method focused on its application in MRI follow-up studies; the method provides a high scan-rescan reliability, which was tested on healthy subject data. Scan-rescan reliability coefficients of variation (COV) were below 1 %, intra- and interrater COV were even lower (0.1-0.2 %). To show the applicability in longitudinal trials, 3-year follow-up data of 48 patients with a progressive course of MS were assessed. In this cohort, CSCV loss was the only significant predictor of disability progression (p = 0.02). We are, therefore, confident that our method provides a reliable tool for SC volumetry in longitudinal clinical trials.


Assuntos
Medula Cervical/patologia , Processamento de Imagem Assistida por Computador , Imagem por Ressonância Magnética , Esclerose Múltipla/patologia , Adulto , Idoso , Medula Cervical/diagnóstico por imagem , Avaliação da Deficiência , Progressão da Doença , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/diagnóstico por imagem , Reprodutibilidade dos Testes , Adulto Jovem
19.
Platelets ; 27(7): 668-672, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27065056

RESUMO

Testing of P2Y12-receptor antagonist effects can support clinical decision-making. However, most platelet function assays use only ADP as agonist which is not P2Y12-receptor specific. For this reason P2Y12-receptor specific assays have been developed by adding prostaglandin E1 (PGE1) to reduce ADP-induced platelet activation via the P2Y1-receptor. The present study sought to evaluate a P2Y12-receptor specific assay for determination of pharmacodynamic and clinical outcomes. This study enrolled 400 patients undergoing coronary stenting after loading with clopidogrel or prasugrel. ADP-induced platelet reactivity was assessed by whole blood aggregometry at multiple time points with a standard ADP assay (ADPtest) and a P2Y12-receptor specific assay (ADPtest HS, both run on Multiplate Analyzer, Roche Diagnostics). Patients were clinically followed for 1 month and all events adjudicated by an independent committee. In total, 2084 pairs of test results of ADPtest and ADPtest HS were available showing a strong correlation between results of both assays (r = 0.96, p < 0.001). These findings prevailed in multiple prespecified subgroups (e.g., age; body mass index; diabetes). Calculated cutoffs for ADPtest HS and the established cutoffs of ADPtest showed a substantial agreement for prediction of ischemic and hemorrhagic events with a Cohen's κ of 0.66 and 0.66, respectively. The P2Y12-receptor specific ADPtest HS assay appears similarly predictive for pharmacodynamic and clinical outcomes as compared to the established ADPtest assay indicating its applicability for clinical use. Further evaluation in large cohorts is needed to determine if P2Y12-receptor specific testing offers any advantage for prediction of clinical outcome.


Assuntos
Plaquetas/metabolismo , Agregação Plaquetária , Testes de Função Plaquetária , Receptores Purinérgicos P2Y12/metabolismo , Idoso , Plaquetas/efeitos dos fármacos , Comorbidade , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/complicações , Doença da Artéria Coronariana/terapia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Intervenção Coronária Percutânea/efeitos adversos , Intervenção Coronária Percutânea/métodos , Agregação Plaquetária/efeitos dos fármacos , Inibidores da Agregação de Plaquetas/farmacologia , Testes de Função Plaquetária/métodos , Testes de Função Plaquetária/normas , Antagonistas do Receptor Purinérgico P2Y/farmacologia , Reprodutibilidade dos Testes , Fatores de Risco
20.
Neuroimage ; 134: 281-294, 2016 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-27039700

RESUMO

A concern for researchers planning multisite studies is that scanner and T1-weighted sequence-related biases on regional volumes could overshadow true effects, especially for studies with a heterogeneous set of scanners and sequences. Current approaches attempt to harmonize data by standardizing hardware, pulse sequences, and protocols, or by calibrating across sites using phantom-based corrections to ensure the same raw image intensities. We propose to avoid harmonization and phantom-based correction entirely. We hypothesized that the bias of estimated regional volumes is scaled between sites due to the contrast and gradient distortion differences between scanners and sequences. Given this assumption, we provide a new statistical framework and derive a power equation to define inclusion criteria for a set of sites based on the variability of their scaling factors. We estimated the scaling factors of 20 scanners with heterogeneous hardware and sequence parameters by scanning a single set of 12 subjects at sites across the United States and Europe. Regional volumes and their scaling factors were estimated for each site using Freesurfer's segmentation algorithm and ordinary least squares, respectively. The scaling factors were validated by comparing the theoretical and simulated power curves, performing a leave-one-out calibration of regional volumes, and evaluating the absolute agreement of all regional volumes between sites before and after calibration. Using our derived power equation, we were able to define the conditions under which harmonization is not necessary to achieve 80% power. This approach can inform choice of processing pipelines and outcome metrics for multisite studies based on scaling factor variability across sites, enabling collaboration between clinical and research institutions.


Assuntos
Artefatos , Encéfalo/anatomia & histologia , Interpretação de Imagem Assistida por Computador/instrumentação , Interpretação de Imagem Assistida por Computador/métodos , Imagem por Ressonância Magnética/instrumentação , Imagem por Ressonância Magnética/métodos , Modelos Estatísticos , Algoritmos , Simulação por Computador , Desenho de Equipamento , Análise de Falha de Equipamento , Europa (Continente) , Humanos , Aumento da Imagem/instrumentação , Aumento da Imagem/métodos , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Estados Unidos
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