Population & Clinical Neuroepidemiology

Dr. Dr. Ahmad Aziz

Areas of investigation/research focus

Using deep (endo)phenotypic data obtained in the context of both population-based and clinical cohort studies, we aim to identify the risk factors, causes as well as trait and state markers of neurodegenerative diseases through application of epidemiological and bio-informatics approaches. Currently, the focus of my group is on the following three projects:

Tandem repeats associated with neurogenomic somatic instability and neurodegeneration

Dementia and other neurodegenerative diseases are among the leading causes of disability worldwide and have an immense societal impact due to lack of effective treatments. For developing better preventive and therapeutic strategies, it is essential to clarify their still largely elusive genetic basis and pathophysiology. Emerging insights from the study of rare hereditary repeat expansion disorders, like Huntington disease and many spinocerebellar ataxias, caused by elongations of repetitive DNA sequences (‘tandem repeats’ (TRs)) indicate that TRs could induce instability of neuronal DNA (‘neurogenomic somatic instability’), and thereby instigate molecular changes that lead to neuronal degeneration. However, the role of highly prevalent TR variations or their somatic instability in the pathogenesis of common age-associated neurodegenerative diseases is unknown.

Therefore, a major focus of my group is to assess the role of TRs and their somatic instability in the pathogenesis of neuronal degeneration, the defining hallmark of all neurodegenerative diseases. To this end, we: 1) apply genome-wide profiling to systematically identify TRs whose size or somatic instability are related to neuronal degeneration in the general population and/or disease severity in repeat expansion disorders, using an innovative approach combining ‘liquid biopsy’ of neuronal tissue, high-throughput ultra-deep long-read DNA sequencing and ultrasensitive biomarkers of neuronal degeneration, 2) delineate the neuroanatomical pathways affected by TR somatic instability through comprehensive neuroimaging analyses, and 3) disentangle the underlying molecular and cellular mechanisms, using an extensive integrative multi-omics approach with experimental validation in neuronal cell lines and post-mortem human brain tissue.

Elucidation of the neuroanatomical basis of motor function across lifespan.

Deterioration of motor function is an early feature of many neurodegenerative diseases, whereas physical activity may protect against neurodegeneration and cognitive decline. Elucidating the neuroanatomical basis of motor dysfunction across lifespan is thus crucial for both identification of early markers of, and development of more effective preventive and therapeutic strategies against, neurodegenerative diseases. Therefore, here we aim to assess the relation between accelerometer-based physical activity, as well as inertial motion sensor-based whole-body motor performance, with structural integrity and connectivity of relevant brain regions across lifespan in the population-based Rhineland Study.

Hypothalamic dysfunction as a driver of age-related cognitive decline.

The hypothalamus is the body’s principal homeostatic center and plays a crucial role in the modulation of cognition. However, whether hypothalamic pathology could be a risk factor for or marker of cognitive decline has not been studied in the general population for lack of a scalable high-throughput analysis method. Therefore, in this project we are developing a novel automated parcellation procedure to accurately delineate hypothalamic structures on MR images, and aiming to apply this method to relate various measures of hypothalamic structural and functional integrity to cognitive function in the population-based Rhineland Study.

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