In humans, autopsy studies on elderly subjects who have not been diagnosed with a neurodegenerative disease reported tau and amyloid deposits and it still stays unclear what causes these deposits and what are their contributions to neurodegeneration. Animal studies suggest that influence from the circulatory system can either accelerate or slow brain aging and cognitive function. Aging is a complex process, comprising an interplay of different cell-intrinsic and local as well as environmental factors. In this context, better understanding the physiological processes of aging, their delineation, and turning points into actual brain disease is essential. However, the reasons for the development of neurodegenerative diseases are still of current debate and the detection of early biomarkers predicting brain disease and cognitive impairment is moving more and more into focus of current research. Given the perspective of current demographic trends, neurodegenerative diseases are expected to affect a rising number of people in the future, together with a significantly increased affected lifetime of patients. Baseline findings will be used as underlying basis for the further implications of aging and neuronal degeneration as well as examination of brain aging under different aspects of brain pathology versus physiological aging. We show that intra-subject across-test variability as a marker of neuropsychological test performance as well as age, gender, and combined risk factors influence neuronal decline as represented by decrease in brain volume, cortical thickness, and increase in white matter lesions. We here describe the study protocol and baseline findings of the SENIOR observational study which aim is the establishment of integrated, multiparametric maps of normal aging and the identification of early biomarkers for neurodegeneration. There is no difference between the lower- and higher-risk groups in amyloid load using PET data from a subset of 81 subjects. Division of the cohort into subjects with a higher and lower risk profile shows significant differences in intra-subject across-test variability and volumes as well as cortical thickness of brain regions of the temporal lobe. Intra-subject across-test variability as a measure of neuropsychological test performance and possible cognitive marker predicts white matter volume and is significantly associated with risk profile. Cardiovascular risk factors were strongly associated with juxtacortical and periventricular lesions. Baseline results with multiple regression analyses reveal that cerebral white matter lesions can be predicted by cardiovascular and cognitive risk factors and age. One hundred forty-two participants (50% females) were enrolled in the SENIOR cohort with a mean age of 60 (SD 6.3) years at baseline. Our multimodal protocol includes structural, diffusion, functional, and sodium magnetic resonance imaging (MRI) at 3 T and 7 T, positron emission tomography (PET), blood samples, genetics, audiometry, and neuropsychological and neurological examinations as well as assessment of neuronal risk factors. The SENIOR study represents a longitudinal, observational study including cognitively healthy elderlies aged between 50 and 70 years old at the time of inclusion, being followed annually over 10 years. In this context, understanding physiological aging and its turning point into neurodegeneration is essential for the development of possible biomarkers and future therapeutics of brain disease. Current demographic trends point towards an aging society entailing increasing occurrence and burden of neurodegenerative diseases.
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