Striatal Blood–Brain Barrier Opening in Parkinson's Disease Dementia: A Pilot Exploratory Study

Abstract Background Parkinson's disease (PD) exhibits a high prevalence of dementia as disease severity and duration progress. Focused ultrasound (FUS) has been applied for transient blood–brain barrier (BBB) opening of cortical regions in neurodegenerative disorders. The striatum is a primary target for delivery of putative therapeutic agents in PD. Objective Here, we report a prospective, single‐arm, nonrandomized, proof‐of‐concept, phase I clinical trial (NCT03608553 amended) in PD with dementia to test the safety and feasibility of striatal BBB opening in PD patients. Methods Seven PD patients with cognitive impairment were treated for BBB opening in the posterior putamen. This was performed in two sessions separated by 2 to 4 weeks, where the second session included bilateral putamina opening in 3 patients. Primary outcome measures included safety and feasibility of focal striatal BBB opening. Changes in motor and cognitive functions, magnetic resonance imaging (MRI), 18 F‐fluorodopa (FDOPA), and β‐amyloid PET (positron emission tomography) images were determined. Results The procedure was feasible and well tolerated, with no serious adverse events. No neurologically relevant change in motor and cognitive (battery of neuropsychological tests) functions was recognized at follow‐up. MRI revealed putamen BBB closing shortly after treatment (24 hours to 14 days) and ruled out hemorrhagic and ischemic lesions. There was a discrete but significant reduction in β‐amyloid uptake in the targeted region and no change in FDOPA PET. Conclusions These initial results indicate that FUS‐mediated striatal BBB opening is feasible and safe and therefore could become an effective tool to facilitate the delivery of putative neurorestorative molecules in PD. © 2022 International Parkinson and Movement Disorder Society.