Longitudinal multi-modal imaging in progressive supranuclear palsy syndromes - PROJECT SUMMARY Progressive supranuclear palsy (PSP) is a devastating neurodegenerative disorder characterized by deposition of the protein 4-repeat (4R) tau in key brainstem and subcortical nuclei, including the substantia nigra, red nucleus, subthalamic nucleus, pallidum, thalamus and basal ganglia. Patients typically present with postural instability with falls, ocular motor impairments and parkinsonism, although there is a large degree of clinical heterogeneity in presenting syndrome and disease progression. In the 2nd cycle, we demonstrated volume loss and tau PET uptake in these key nuclei across different PSP clinical syndromes, albeit with some heterogeneity, although there are many gaps in knowledge regarding the role of these brainstem and subcortical nuclei in disease progression. The goal of the 3rd cycle is to determine the role of brainstem and subcortical nuclei in disease progression across the PSP clinical spectrum. To address this goal, we will investigate relationships between different pathophysiological abnormalities in these nuclei and disrupted brain connectivity, clinical decline and disease biomarkers measured in blood. In aim 1, we will use novel ultra-high field strength MRI (7T) to measure iron in these nuclei using quantitative susceptibility mapping (QSM) and dopaminergic depletion of the substantia nigra using neuromelanin-sensitive MRI. We will evaluate whether these pathophysiological abnormalities change over time, vary across the PSP clinical spectrum, and relate spatially and temporally to volume loss, tau uptake and disruptions in brain connectivity. We will measure breakdowns in structural connectivity using diffusion tractography with neurite orientation dispersion and density imaging (NODDI) and breakdowns in functional connectivity using resting-state fMRI. In aim 2, we will determine how pathophysiological abnormalities in these nuclei measured on neuroimaging and at autopsy are related to survival and progression in key clinical features (gait, parkinsonism, ocular motor impairment, dysphagia and cognition). In aim 3, we will assess plasma neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) that provide markers of neuroaxonal injury and astrogliosis, and plasma markers of tau, and determine whether these plasma metrics relate to pathophysiological abnormalities in the brainstem and subcortical nuclei and clinical progression across the PSP spectrum. To achieve our goals, we will recruit 100 PSP patients and utilize data from 95 autopsy-confirmed PSP cases. Each patient will undergo clinical and dysphagia evaluations, 3T MRI that includes structural MRI, diffusion MRI and resting-state MRI; 7T MRI that includes QSM and neuromelanin-sensitive MRI; and flortaucipir PET. All patients will undergo three serial assessments one year apart. The results of this grant will improve understanding of disease mechanisms, identify potential mechanistic treatment targets for the disease, and provide biomarkers for diagnosis, prognosis and tracking disease progression across the PSP clinical spectrum.
