Kurzfassung

Substantial progress has been made over the last decade concerning the understanding of AD pathomechanisms, with regard to diagnostic tools (biomarkers and imaging), and the development of disease modifying drugs specifically targeting the amyloidogenic pathway. However, effective secondary preventive treatments are still lacking. Promising substances failed to show efficacy in clinical phase II or III trials although their mechanisms of action had been demonstrated in vitro, in transgenic...Substantial progress has been made over the last decade concerning the understanding of AD pathomechanisms, with regard to diagnostic tools (biomarkers and imaging), and the development of disease modifying drugs specifically targeting the amyloidogenic pathway. However, effective secondary preventive treatments are still lacking. Promising substances failed to show efficacy in clinical phase II or III trials although their mechanisms of action had been demonstrated in vitro, in transgenic animal studies, or even in subsets of AD patients 8. One important reason for this failure is that the initiation of disease modifying treatment in the clinical stages of symptomatic AD is already too late given the decades of disease development before. PET studies suggest that amyloid deposition has already reached a plateau before the onset of the dementia syndrome 9. If cerebral amyloidosis plays a key role in the development of clinical AD it might be promising to reduce cerebral amyloid in the MCI state or even before the onset of clinical symptoms, namely in healthy elderly (HE) who are at high risk to develop symptoms within a short time interval. The long preclinical phase of AD provides a promising window for intervention with disease-modifying therapy. To this end it will be indispensable to diagnostically capture the link between the pathophysiological process of AD and the emergence of the clinical symptoms. The present study has been designed to bridge the gap between the specific diagnostic finding of cerebral amyloid (molecular phenotype) in MCI and the prediction of the individual risk for prodromal AD (clinical phenotype) by multimodal imaging. The study aims to predict short term (18 months) cognitive decline and development of clinical AD symptoms based on MR-measures of FC and structural connectivity in a group of amnestic MCI subjects with elevated cerebral amyloid burden (as measured by 18F-based amyloid PET (flutemetamol). To standardize the study internal amyloid-imaging, we will include a group of AD dementia subjects.
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