Increasing evidence recognizes Alzheimer's disease (AD) as a multifactorial and heterogeneous disease with multiple contributors to its pathophysiology, including vascular dysfunction. The recently... Show moreIncreasing evidence recognizes Alzheimer's disease (AD) as a multifactorial and heterogeneous disease with multiple contributors to its pathophysiology, including vascular dysfunction. The recently updated AD Research Framework put forth by the National Institute on Aging-Alzheimer's Association describes a biomarker-based pathologic definition of AD focused on amyloid, tau, and neuronal injury. In response to this article, here we first discussed evidence that vascular dysfunction is an important early event in AD pathophysiology. Next, we examined various imaging sequences that could be easily implemented to evaluate different types of vascular dysfunction associated with, and/or contributing to, AD pathophysiology, including changes in blood-brain barrier integrity and cerebral blood flow. Vascular imaging biomarkers of small vessel disease of the brain, which is responsible for >50% of dementia worldwide, including AD, are already established, well characterized, and easy to recognize. We suggest that these vascular biomarkers should be incorporated into the AD Research Framework to gain a better understanding of AD pathophysiology and aid in treatment efforts. (C) 2018 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved. Show less
Herrera-Gomez, F.; Aguila, W. del; Tejero-Pedregosa, A.; Adler, M.; Padilla-Berdugo, R.; Maurtua-Briseno-Meiggs, A.; ... ; Lambert, C. 2018
Discovery and development of Central Nervous System (CNS) drugs is hampered by high attrition rates. One of the reasons is the lack of blood-based biomarkers that represent the interaction between... Show moreDiscovery and development of Central Nervous System (CNS) drugs is hampered by high attrition rates. One of the reasons is the lack of blood-based biomarkers that represent the interaction between the drug and the neurological systems of interest. Here we present a systems-pharmacology approach that combines a multi-biomarker approach (e.g. metabolomics) with pharmacokinetic/pharmacodynamic (PK/PD) modeling to reveal quantitative pharmacological characteristics that are relevant to dopaminergic drug action. Moreover, we set out to identify biomarkers that can be obtained from the blood as non-invasive sampling site. In the first section of this thesis the methodology is introduced in the context of translational CNS drug development. Moreover, a systematic search is performed to available biomarkers of dopaminergic drug action. Then, in the second part, the multi-biomarker PK/PD approach is applied to biomarkers from the neuroendocrine system as connection between brain and blood. In the third section, the methodology is developed using the simultaneous, time-resolved metabolomics response in brain extracellular fluid and plasma. By applying multi-biomarker PK/PD modeling we revealed quantitative pharmacological characteristics of dopaminergic drugs with regard to multiple biological processes. Moreover, we identified potential blood-based biomarkers of dopaminergic effect in the brain. Show less
The aim of this thesis was to explore the neuromechanics of recovery of arm-hand function after stroke. A literature review revealed six articles that measured biomechanical and electromyographical... Show moreThe aim of this thesis was to explore the neuromechanics of recovery of arm-hand function after stroke. A literature review revealed six articles that measured biomechanical and electromyographical outcome measures simultaneously, while applying active and passive tasks and multiple movement velocities to separate neural and non-neural contributors to movement disorders after stroke. Therefore, a neuromechanic assessment protocol was developed. Parameters were responsive to clinical status and had good to excellent test-retest reliability. Selective muscle activation was assessed with high measurement reliability and was significantly lower in chronic stroke patients compared to healthy participants. Longitudinally, neuromechanical parameters were combined with data on arm-hand function at six months after stroke. Paresis and diminished modulation of reflexes were associated with poor functional outcome. Changes in tissue properties were represented by a shift in wrist rest angle towards flexion and decline in passive range of motion. Increase in active range of motion and steady rest angle contributed most to prediction of functional outcome. The precision diagnostics provided by a neuromechanical assessment protocol could support clinical decision making and should be used in prediction models and as biomarkers in recovery of arm-hand function after stroke, for example by improving the selection of time-window and patients. Show less
This thesis focused on different aspects of melanoma treatment with immunotherapy and targeted therapy. In chapter 2 we search for biomarkers that could be associated with overall survival in... Show moreThis thesis focused on different aspects of melanoma treatment with immunotherapy and targeted therapy. In chapter 2 we search for biomarkers that could be associated with overall survival in patients treated with ipilimumab. In chapter 3 we describe diarrea, a commonly seen side effect of immunotherapy. Here we show that there is no significant correlation between grade of diarrhea and severity of colitis as seen during endoscopy. Chapters 4 and 5 describe patients with brain metastases and/or leptomeningeal metastases. In chapter 4 we show the difference in overall survival in patients treated with vemurafenib, dabrafenib or the combination of dabrafenib + trametinib. Chapter 5 focusses on the treatment of leptomeningeal metastases. Here a significant difference in overall survival was noted between treated and untreated patients. Furthermore LDH was a predictive biomarker for overall survival. In chapter 6 we show that treating patients with vemurafenib beyond progression of disease has a significant impact on overall survival. Lastly in chapter 7 we review the past, present and future of treating patients with different kinds of cancer with tumor-infiltrating lymphocytes. Show less
Stalenhoef, J.E.; Nieuwkoop, C. van; Wilson, D.C.; Starre, W.E. van der; Delfos, N.M.; Leyten, E.M.S.; ... ; Dissel, J.T. van 2018
This thesis consists of two parts addressing novel imaging technologies to improve the treatment of cancer patients. In part I, the additional value of real time image guidance during surgery is... Show moreThis thesis consists of two parts addressing novel imaging technologies to improve the treatment of cancer patients. In part I, the additional value of real time image guidance during surgery is discussed and the research described in this part of the thesis showed that imaging performed during surgery can be of great value. Nevertheless, the success rate is highly dependent on the choice of imaging modality and biomarker to be targeted. In part II, a necrosis avid probe was successfully evaluated as novel method for early neoadjuvant treatment response monitoring. Show less
Cardiovascular magnetic resonance imaging is an important noninvasive imaging modality for the diagnosis, clinical work‐up and treatment planning in patients suspected for a wide range of... Show moreCardiovascular magnetic resonance imaging is an important noninvasive imaging modality for the diagnosis, clinical work‐up and treatment planning in patients suspected for a wide range of cardiovascular pathology. CMR imaging is accurate and reliable, and provides invaluable information to evaluate the cardiovascular system without the need of ionizing radiation. The studies described in this thesis evaluate new CMR imaging techniques in clinical practice and explore the prognostic value of new CMR imaging biomarkers in patients with symptomatic peripheral arterial occlusive disease. New advances and innovations in MR imaging technology improve and further expand the clinical applications of cardiovascular imaging in daily clinical practice. In this thesis, a new, fast free‐breathing 2D delayed‐enhancement MRI sequence is validated and demonstrated to be a reliable tool for detecting myocardial infarction. Furthermore, new technical developments allow single‐injection, three‐station, moving‐table MRA protocol at 3Tesla with similar diagnostic performance when compared to 1.5Tesla. Additionally, submillimeter isotropic voxel acquisition in the lower legs at 1.5Tesla improves the diagnostic accuracy and depicts more open infragenual arterial segments.Additionally, it is demonstrated that new MRI biomarkers as distal aortic pulse wave velocity statistically significantly correlate with stenosis severity in symptomatic patients with peripheral arterial occlusive disease. Finally, we showed that CMR derived biomarkers relating to stenosis severity, aortic stiffness and left ventricular function play a role in prognosis of outcome in patients with symptomatic PAOD. In the future, incorporation of the described new MRI biomarkers in the clinical workup of peripheral arterial occlusive disease may play an important role for full vascular risk assessment and ultimately, patients may benefit in clinical practice. Show less
Swets, M.; Kuppen, P.J.K.; Blok, E.J.; Gelderblom, H.; Velde, C.J.H. van de; Nagtegaal, I.D. 2018
IntroductionThe Alzheimer's Disease Research Summits of 2012 and 2015 incorporated experts from academia, industry, and nonprofit organizations to develop new research directions to transform our... Show moreIntroductionThe Alzheimer's Disease Research Summits of 2012 and 2015 incorporated experts from academia, industry, and nonprofit organizations to develop new research directions to transform our understanding of Alzheimer's disease (AD) and propel the development of critically needed therapies. In response to their recommendations, big data at multiple levels are being generated and integrated to study network failures in disease. We used metabolomics as a global biochemical approach to identify peripheral metabolic changes in AD patients and correlate them to cerebrospinal fluid pathology markers, imaging features, and cognitive performance.MethodsFasting serum samples from the Alzheimer's Disease Neuroimaging Initiative (199 control, 356 mild cognitive impairment, and 175 AD participants) were analyzed using the AbsoluteIDQ-p180 kit. Performance was validated in blinded replicates, and values were medication adjusted.Results Multivariable-adjusted analyses showed that sphingomyelins and ether-containing phosphatidylcholines were altered in preclinical biomarker-defined AD stages, whereas acylcarnitines and several amines, including the branched-chain amino acid valine and α-aminoadipic acid, changed in symptomatic stages. Several of the analytes showed consistent associations in the Rotterdam, Erasmus Rucphen Family, and Indiana Memory and Aging Studies. Partial correlation networks constructed for Aβ1–42, tau, imaging, and cognitive changes provided initial biochemical insights for disease-related processes. Coexpression networks interconnected key metabolic effectors of disease.DiscussionMetabolomics identified key disease-related metabolic changes and disease-progression-related changes. Defining metabolic changes during AD disease trajectory and its relationship to clinical phenotypes provides a powerful roadmap for drug and biomarker discovery. Show less
The work described in this thesis presents part of a framework that can be used to extract detailed disease biological information from peripheral tissue. This framework is based on the... Show moreThe work described in this thesis presents part of a framework that can be used to extract detailed disease biological information from peripheral tissue. This framework is based on the central dogma of biology “DNA to RNA to protein” and on a systems biology approach that aims to produce synergetic data whose disease pathological, prognostic and predictive value is greater than the sum of the individual experiment results. HD patients are often characterized by a multifaceted clinical profile, consisting of several symptoms and variable disease progression rates. Therefore, a systems approach such as the one described above is expected to be the most effective in identifying potential treatments and predictive biomarkers that will be most informative for the different patient subpopulations. Show less
This thesis demonstrates the application of bioinformatics to investigate the mechanisms that are implicated in Huntington’s Disease (HD). HD is an inherited neurodegenerative disorder and although... Show moreThis thesis demonstrates the application of bioinformatics to investigate the mechanisms that are implicated in Huntington’s Disease (HD). HD is an inherited neurodegenerative disorder and although the cause of the disease is known since 1993 we are still lacking a cure or treatment that can effectively treat the symptoms of HD. In order to tackle such a complicated case study, we followed a multidisciplinary approach to exploit the expertise and knowledge of people with diverse scientific background (chapter 2). This blend of disciplines facilitates constant collaboration between bioinformaticians, wet lab technicians, biologists, computer engineers and data scientists. A collaborative eScience model is proposed as a way to combine state-of-the-art computation analysis and laboratory work (chapter 3). At the same time, we explored methods to preserve the results, materials and methods involved in the experiment to increase the reproducibility and reusability of our research (chapter 4). In chapter 5 we identified disease signatures in blood that are functionally similar to signatures in brain. These are proposed as candidate biomarkers to be used as a monitoring tool for the state of the disease in brain, but also as a means to determine whether a treatment is successful or not. Show less
