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
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
Globally more than 200,000 people develop leprosy every year and 2-3 million people live with leprosy associated disabilities. Despite the availability of multi drug therapy, leprosy has continued... Show moreGlobally more than 200,000 people develop leprosy every year and 2-3 million people live with leprosy associated disabilities. Despite the availability of multi drug therapy, leprosy has continued affecting many individuals, including children because of the uninterrupted transmission in the population. Untreated multi bacillary cases as well as non-symptomatic M. leprae infected individuals in the population are believed to be the major sources of M. leprae infection and transmission. Leprosy reactions are also the major causes of disabilities. However, no tools are available to predict their occurrence. This thesis focuses on in vitro assessment of recombinant M. leprae proteins and synthetic peptides for their immunogenicity and specificity in populations with different genetic backgrounds by measuring cell mediated immunity and this has shown the presence of potential antigens. Further in depth analysis of the host immune responses against these unique antigens in leprosy patients, their household contacts and healthy endemic controls has led to identification of potential biomarkers with an immense importance in development of diagnostic tools for detection of M. leprae infection and early diagnosis of leprosy reactions. Currently, field friendly tests for early detection are developed at the LUMC using identified M. leprae antigens and host biomarkers with diagnostic potential. Show less
Wijdeven, R.H.; Pang, B.X.; Assaraf, Y.G.; Neefjes, J. 2016
This thesis describes attempts to identify novel pathophysiology based biomarkers for chronic airway disease by applying newer detection techniques. It appears that such an approach may be... Show moreThis thesis describes attempts to identify novel pathophysiology based biomarkers for chronic airway disease by applying newer detection techniques. It appears that such an approach may be worthwhile to pursue. Further, it shows that application of biomarkers allows effective development of new therapies in chronic airway disease. Show less
Mayboroda, O.A.; Hooij, A. van; Derks, R.; Eeden, S.J.F. van den; Dijkman, K.; Khadge, S.; ... ; Geluk, A. 2016
Conclusions: This study indicates that urinary metabolic profiles are promising host biomarkers for the detection of intra-individual changes during acute inflammation in leprosy and could... Show moreConclusions: This study indicates that urinary metabolic profiles are promising host biomarkers for the detection of intra-individual changes during acute inflammation in leprosy and could contribute to early treatment and prevention of tissue damage. (C) 2016 The Authors. Published by Elsevier Ltd on behalf of International Society for Infectious Diseases. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Show less
Oonk, S.; Spitali, P.; Hiller, M.; Switzar, L.; Dalebout, H.; Calissano, M.; ... ; Burgt, Y.E.M. van der 2016
In this thesis the epidemiology of suicidal ideation and suicide attempts (together referred to as 'suicidality') in Huntington's disease (HD) is investigated and coping styles and support... Show moreIn this thesis the epidemiology of suicidal ideation and suicide attempts (together referred to as 'suicidality') in Huntington's disease (HD) is investigated and coping styles and support strategies that may serve to help suicidal HD mutation carriers are explored. Suicidality frequently occurs in HD, with a 1-month prevalence of up to 20%. Mutation carriers who were most likely to currently experience suicidal ideation or suicidality had a shorter disease duration, were anxious, aggressive, previously attempted suicide, used antidepressants, and had a depressed mood. The presence of a depressed mood and use of benzodiazepines were the only significant independent predictors of incident suicidal ideation or suicidality. Biological parameters, in particular functioning of the immune system and the hypothalamus-pituitary-adrenal axis were not found to be associated with suicidality in HD. In a qualitative study it was shown that suicidal HD mutation carriers generally used four strategies to cope with suicidality: talking about suicidality, employing self-management activities, using medication, and discussing end-of-life wishes. Lastly, in a meta-analysis, we examined whether the expression of suicidal ideation predicted subsequent completed suicide. Effect estimates differed substantially among different populations, but none of the included studies investigated this association in HD. Show less
Aim of this thesis was to provide evidence for the clinical implication of biomarkers in blood and urine, as well as genetic markers, for the prediction of the severity and course of febrile UTI.... Show moreAim of this thesis was to provide evidence for the clinical implication of biomarkers in blood and urine, as well as genetic markers, for the prediction of the severity and course of febrile UTI. Furthermore, this thesis focused on optimization of antimicrobial treatment of febrile UTI. The main results are: 1. Recent hospitalization, indwelling urinary catheter and especially individual fluoroquinolone (FQ) use are independent risk factors for a FQ-resistant Escherichia coli febrile UTI. 2. Women with febrile UTI, including postmenopausal women and those with comorbidities, can be safely and successfully treated with a 7-day course of oral ciprofloxacin. In men, however, treatment duration should be at least 14 days. 3. Diabetes mellitus does not affect the clinical presentation and course of febrile UTI; concurrent illnesses and higher age of the diabetic population attribute to a more complicated course. 4. MR-proADM more accurately predicts a complicated course of disease than currently available inflammatory biomarkers. Importantly, biomarkers derived directly from host defense mechanisms are not suitable to distinguish between febrile UTI patients with and without bacteremia. 5. MP-TF activity is related to disease severity and bacteraemia in febrile E. coli UTI and may contribute to the prothrombotic state in gram-negative sepsis. Show less