On the Origin of Dementia : a Population Perspective on Risk and Aetiology

Recent years have seen a surge in dementia research, with increasing awareness that preventive strategies are key to curbing the dementia epidemic. Drawing from long-term population-based studies, this thesis describes the burden of dementia in terms of (healthy) life years lost, lifetime risk of developing disease, and the past and potential effects of preventive interventions on dementia incidence. Furthermore, the role of (disturbances in) cerebral blood flow, for instance due to carotid artery stenosis, and that of cerebral autoregulatory mechanisms in the onset of dementia is extensively discussed. In the subsequent chapter, a literature review that ties coronary heart disease and heart failure to the risk of dementia is followed by exploration of potential underlying mechanisms, including thromboembolic disease (e.g. Von Willebrand factor and ADAMTS13), (vascular) amyloid-β, and aortic valve calcification. Finally, the heritability of dementia and Alzheimer’s disease is yielded for both aetiological and predictive purposes. In particular, the role of the Apolipoprotein E (APOE) gene is described in mortality and for clinical trial design, followed by the use of parental family history and common genetic variants for risk prediction. This thesis concludes with methodological considerations and recommendations – or rather a wish list – for future research to strive and take dementia into the realm of forgotten diseases

Protocol TOP-Study (tacrolimus organ perfusion): a prospective randomized multicenter trial to reduce ischemia reperfusion injury in transplantation of marginal liver grafts with an "ex vivo" tacrolimus perfusion

Background: Critical organ shortage results in the utilization of extended donor criteria (EDC) liver grafts. These marginal liver grafts are prone to increased ischemia reperfusion injury (IRI) which may contribute to deteriorated graft function and survival. Experimental data have shown that the calcineurin inhibitor tacrolimus exerts protective effects on hepatic IRI when applied intravenously or directly as a hepatic rinse. Therefore, the aim of the present study is to examine the effects of an ex vivo tacrolimus perfusion on IRI in transplantation of EDC liver grafts. Methods/Design: The TOP-Study (tacrolimus organ perfusion) is a randomized multicenter trial comparing the ex vivo tacrolimus perfusion of marginal liver grafts with placebo. We hypothesize that a tacrolimus rinse reduces IRI, potentially improving organ survival following transplantation of EDC livers. The study includes livers with two or more EDC, according to Eurotransplant International Foundation’s definition of EDC livers. Prior to implantation, livers randomized to the treatment group are rinsed with tacrolimus at a concentration of 20 ng/ml in 1000 ml Custodiol solution and in the placebo group with Custodiol alone. The primary endpoint is the maximum serum alanine transamninase (ALT) level within the first 48 hours after surgery; however, the study design also includes a 1-year observation period following transplantation. The TOP-Study is an investigator-initiated trial sponsored by the University of Munich Hospital. Seven other German transplant centers are participating (Berlin, Frankfurt, Heidelberg, Mainz, Münster, Regensburg, Tübingen) and aim to include a total of 86 patients. Discussion: Tacrolimus organ perfusion represents a promising strategy to reduce hepatic IRI following the transplantation of marginal liver grafts. This treatment may help to improve the function of EDC grafts and therefore safely expand the donor pool in light of critical organ shortage. Trial register: EudraCT number: 2010-021333-31, ClinicalTrials.gov identifier: NCT0156409