Brain network dependent propagation of tau-pathology in Alzheimer disease

• Applicant: Professor Dr. Alexander Drzezga
• Subject Area: Clinical Neurology; Neurosurgery and Neuroradiology ; Clinical Psychiatry, Psychotherapy, Child and Adolescent Psychiatry ; Nuclear Medicine, Radiotherapy, Radiobiology
• Term: since 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 329109473

In Alzheimer disease, two major forms of protein aggregation, discussed as potential causal factors of disease, are the extracellular deposits of beta-amyloid (amyloid-plaques) and the intracellular aggregates of tau-protein (neurofibrillary tangles). In the past years, research on Alzheimer disease has been has been strongly focused on amyloid-pathology. However, more recently, tau-aggregation pathology is moving into the focus of attention, particularly as numerous clinical trials aiming to reduce amyloid-aggregation pathology have not shown ground-breaking success. It has been suggested that the extent of tau-deposition in the brain correlates more closely to the degree/progression of cognitive impairment as compared to amyloid. A key role of tau-pathology in the pathogenesis appears particularly plausible in the context of the so-called network degeneration hypothesis. The introduction of functional MRI (rsfMRI) resting state connectivity analysis today allows the identification of functional connectivity networks in the brain. The network degeneration hypothesis suggests that the expansion of neurodegeneration follows specific functional connectivity networks across the brain. Recent findings indicate that a prion-like mechanism may be involved in the spreading of tau-pathology. It has been shown that tau-aggregates appear to be capable of trans-synaptic spreading, i.e. to leak out of the synaptic terminal of one specific affected neuron, cross the synaptic cleft and potentially induce further aggregation of tau-proteins in the subsequent connected neuron. This finding would explain why neurodegenerative pathology may show an expansion pattern following functional connectivity pathways across the brain.Consequently, the investigation of deposition of tau-aggregates in vivo over time and its relation to other neurodegenerative pathologies and the functional networks of the brain is of major scientific interest and may aid significantly in the understanding of pathophysiological mechanisms involved in development of Alzheimer disease. Novel molecular imaging tracers for Positron Emission Tomography (PET) allowing to measure tau-aggregates in vivo may be ideally suited to serve this scientific purpose. Thus, in the current study, we will apply a multimodal imaging protocol including rsfMRI, amyloid-PET and tau-PET in subjects with Alzheimer disease and subjects at risk in a longitudinal approach, to address the following hypotheses:1. Tau-pathology expands along neuronal networks of the brain. 2. This expansion of tau pathology leads to progressive functional impairment of affected networks and consecutive network-specific cognitive decline.3. Using a mathematical model integrating baseline tau deposition, amyloid deposition and network architecture, the progression of tau pathology over time can be predicted in the individual patient.

• DFG Programme: Research Grants
• Co-Investigators: Professor Dr. Thilo van Eimeren; Professor Dr. Frank Jessen; Professor Dr. Juraj Kukolja; Professor Dr. Bernd Neumaier; Professor Dr. Marc Tittgemeyer