FUMA · Focused ultrasound and microbubbles targeting alpha-synuclein pathology-related dementia (FUMA)

Over half of Parkinson Disease patients develop cortical dysfunctions leading to Parkinson Disease Dementia (PDD). The cognitive changes are primarily driven by pathological alpha-synuclein (a-syn) protein aggregates with secondary synaptic dysfunctions in the cortex. Microglia plays a key role in synapse maintenance and clearance of aggregated a-syn proteins, however, this is impaired in PD. Low intensity focused ultrasound (FUS) combined with intravenous microbubbles (MB) can non-invasively increase the permeability of the blood-brain barrier, resulting in a transient and controlled entry of blood-born substances. In animal models of Alzheimer disease, FUS-MB treatments increase microglial-mediated clearance of extra- and intracellular protein aggregates and improve synapse health. In small patient cohorts in the clinic, FUS-MB treatments are safe and results suggest decreased levels of pathological proteins in Alzheimer disease patients. HYPOTHESIS: FUS-MB applications targeted to the cortex promote cortical a-syn clearance and synapse maintenance which can prevent or slow the development of dementia in PD.In a mouse model of PDD we will determine the ability of FUS-MB treatment to increase microglial-mediated clearance of a-syn, maintain synapse health, and inhibit the development of cognitive dysfunctions. In addition, we aim to evaluate non-invasive positron emission tomography and magnetic resonance imaging as biomarkers of the effects of FUS-MB treatment. Finally, we will investigate the underlying pathway of potentially beneficial effects of FUS-MB treatments by measuring changes in specific pathways of interest as well as perform an unbiased screen for novel targets.Both the researcher and supervisor have a background in Parkinson disease research. The researcher brings expertise in FUS-MB treatments of mouse models and the supervisor is an expert in preclinical and clinical neuromodulation, the latter with FUS.