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Nielsen M.,Copenhagen University | Ganz M.,Copenhagen University | Lauze F.,Copenhagen University | Pettersen P.C.,CCBR-SYNARC | And 6 more authors.
BMC Cardiovascular Disorders | Year: 2010

Background: Aortic calcification is a major risk factor for death from cardiovascular disease. We investigated the relationship between mortality and the composite markers of number, size, morphology and distribution of calcified plaques in the lumbar aorta.Methods: 308 postmenopausal women aged 48-76 were followed for 8.3 ± 0.3 years, with deaths related to cardiovascular disease, cancer, or other causes being recorded. From lumbar X-rays at baseline the number (NCD), size, morphology and distribution of aortic calcification lesions were scored and combined into one Morphological Atherosclerotic Calcification Distribution (MACD) index. The hazard ratio for mortality was calculated for the MACD and for three other commonly used predictors: the EU SCORE card, the Framingham Coronary Heart Disease Risk Score (Framingham score), and the gold standard Aortic Calcification Severity score (AC24) developed from the Framingham Heart Study cohorts.Results: All four scoring systems showed increasing age, smoking, and raised triglyceride levels were the main predictors of mortality after adjustment for all other metabolic and physical parameters. The SCORE card and the Framingham score resulted in a mortality hazard ratio increase per standard deviation (HR/SD) of 1.8 (1.51-2.13) and 2.6 (1.87-3.71), respectively. Of the morphological x-ray based measures, NCD revealed a HR/SD >2 adjusted for SCORE/Framingham. The MACD index scoring the distribution, size, morphology and number of lesions revealed the best predictive power for identification of patients at risk of mortality, with a hazard ratio of 15.6 (p < 0.001) for the 10% at greatest risk of death.Conclusions: This study shows that it is not just the extent of aortic calcification that predicts risk of mortality, but also the distribution, shape and size of calcified lesions. The MACD index may provide a more sensitive predictor of mortality from aortic calcification than the commonly used AC24 and SCORE/Framingham point card systems. © 2010 Nielsen et al; licensee BioMed Central Ltd.

Karsdal M.A.,Nordic Bioscience A S | Henriksen K.,Nordic Bioscience A S | Bay-Jensen A.C.,Nordic Bioscience A S | Molloy B.,Novartis | And 8 more authors.
Journal of Clinical Pharmacology | Year: 2011

Oral delivery of proteins has been hampered by an array of difficulties. However, promising novel oral delivery systems have been developed. 5-CNAC, formulated with the peptide salmon calcitonin, is in phase III clinical trials for the treatment of osteoporosis or osteoarthritis and could become the first marketed oral peptide. This article reviews key findings and implications from studies undertaken to date with this oral formulation. Findings include these: (1) the optimal calcitonin tablet dose is 0.8 mg; (2) 0.8 mg of oral calcitonin is rapidly absorbed, reaching maximum concentration in 15 to 30 minutes, and is eliminated from plasma with a short half-life - 9 to 15 minutes; (3) the 0.8-mg tablet is more highly absorbed than the marketed nasal formulation, with biomarker levels indicating significantly greater efficacy in suppression of bone resorption; (4) drug absorption is increased with dosing at least 10 minutes before a meal rather than postprandially and also with 50 mL of water; (5) the optimal timing of dosing for osteoporosis therapy is in the evening to mitigate the circadian peak in bone resorption; and (6) the oral formulations of synthetic and recombinant calcitonin have similar pharmacokinetic and pharmacodynamic properties. These key findings may aid researchers in the development of other oral formulations. © 2011 The Author(s).

Henriksen K.,Nordic Bioscience A S | Bohren K.M.,and Hills Inc. | Bay-Jensen A.C.,Nordic Bioscience A S | Karsdal M.A.,Nordic Bioscience A S | And 2 more authors.
Biomarkers | Year: 2010

The success in biomedical sciences such as genomics and proteomics is not paralleled in the medical product development methods. The consequence of this is a lack of translation into improved drug safety and efficacy. Therefore the US Food and Drug Administration (FDA) introduced the Critical Path Initiative in 2004 to modernize drug development and safety pharmacology. Bone is that largest tissue by weight, and is continuously remodelled. Changes in bone turnover lead to complications such as osteoporosis and fracture, that is associated with an increased mortality. Recent findings have identified bone as a possible endocrine organ and the availability of valid biochemical bone markers suggests that assessing bone turnover should also play an important role in general safety pharmacology. © 2010 Informa UK Ltd.

Marques J.,Copenhagen University | Genant H.K.,CCBR-SYNARC | Genant H.K.,University of California at San Francisco | Lillholm M.,Biomediq | Dam E.B.,Biomediq
Magnetic Resonance in Medicine | Year: 2013

A longitudinal study was used to investigate the quantification of osteoarthritis and prediction of tibial cartilage loss by analysis of the tibia trabecular bone from magnetic resonance images of knees. The Kellgren Lawrence (KL) grades were determined by radiologists and the levels of cartilage loss were assessed by a segmentation process. Aiming to quantify and potentially capture the structure of the trabecular bone anatomy, a machine learning approach used a set of texture features for training a classifier to recognize the trabecular bone of a knee with radiographic osteoarthritis. Using cross-validation, the bone structure marker was used to estimate for each knee both the probability of having radiographic osteoarthritis (KL >1) and the probability of rapid cartilage volume loss. The diagnostic ability reached a median area under the receiver-operator-characteristics curve of 0.92 (P < 0.0001), and the prognosis had odds ratio of 3.9 (95% confidence interval: 2.4-6.5). The medians of cartilage loss of the subjects classified as slow and rapid progressors were 1.1% and 4.9% per year, respectively. A preliminary radiological reading of the high and low risk knees put forward an hypothesis of which pathologies the bone marker could be capturing to define the prognosis of cartilage loss. © 2012 Wiley Periodicals, Inc.

Henriksen K.,Nordic Bioscience Biomarkers and Research | Wang Y.,Nordic Bioscience | Sorensen M.G.,Nordic Bioscience Biomarkers and Research | Barascuk N.,Nordic Bioscience Biomarkers and Research | And 8 more authors.
PLoS ONE | Year: 2013

Objective:Alzheimer's disease (AD) is a devastating neurological disease characterized by pathological proteolytic cleavage of tau protein, which appears to initiate death of the neurons. The objective of this study was to investigate whether a proteolytic fragment of the tau protein could serve as blood-based biomarker of cognitive function in AD.Methods:We developed a highly sensitive ELISA assay specifically detecting an A Disintegrin and Metalloproteinase 10 (ADAM10)-generated fragment of tau (Tau-A). We characterized the assay in detail with to respect specificity and reactivity in healthy human serum. We used samples from the Tg4510 tau transgenic mice, which over-express the tau mutant P301L and exhibit a tauopathy with similarities to that observed in AD. We used serum samples from 21 well-characterized Alzheimer's patients, and we correlated the Tau-A levels to cognitive function.Results:The Tau-A ELISA specifically detected the cleavage sequence at the N-terminus of a fragment of tau generated by ADAM10 with no cross-reactivity to intact tau or brain extracts. In brain extracts from Tg4510 mice compared to wt controls we found 10-fold higher levels of Tau-A (p<0.001), which indicates a pathological relevance of this marker. In serum from healthy individuals we found robust and reproducible levels of Tau-A, indicating that the analyte is present in serum. In serum from AD patients an inverse correlation (R2 = 0.46, p<0.001) between the cognitive assessment score (Mattis Dementia Rating Scale (MDRS)) and Tau-A levels was observed.Conclusion:Based on the hypothesis that tau is cleaved proteolytically and then released into the blood, we here provide evidence for the presence of an ADAM10-generated tau fragment (Tau-A) in serum. In addition, the levels of Tau-A showed an inverse correlation to cognitive function, which could indicate that this marker is a serum marker with pathological relevance for AD. © 2013 Henriksen et al.

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