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), 18F‐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.

Putaminal Recombinant Glucocerebrosidase Delivery with Magnetic Resonance–Guided Focused Ultrasound in Parkinson's Disease: A Phase I Study

“…Results from this study support the safety and feasibility of MRgFUS plus GCase for PD and complement the accompanying article by Pineda and colleagues that investigates the safety and feasibility of BBB opening without drug delivery in the bilateral putamen. 30 Putaminal hypermetabolism was reduced 1 month after treatment, suggesting improved striatal dopaminergic metabolism. 31 Hypermetabolism in the putamen, globus pallidus, thalamus, and cerebellum has been shown to correlate with disease progression and to be reduced after effective treatment.…”

BBB opening with focused ultrasound in nonhuman primates and Parkinson’s disease patients: Targeted AAV vector delivery and PET imaging

“…NCT03608553) designed to investigate the safety and feasibility of focal BBB opening in patients with PD. Details of the procedure have been previously reported ( 13 , 14 ). Relevant to this study, the microbubble contrast agent (Luminity) was administered by gravitational infusion instead of intravenous bolus injection.…”

Brain Waste Removal System and Sleep: Photobiomodulation as an Innovative Strategy for Night Therapy of Brain Diseases

“…Pilot studies on rats show that sleep and opened BBB are equally accompanied by BWRS activation, which has an identical effect on the EEG dynamics and makes it possible to identify EEG markers of increased BBB permeability [ 84 ]. Non-invasive technology for assessing the BBB using only EEG is important for monitoring BBB permeability during surgery in order to control the depth of anesthesia and for the analysis of the progression of a number of brain diseases, such as AD and Parkinson’s disease, brain trauma, diabetic and COVID-19 cerebrovascular injuries, and depression [ 16 , 85 , 86 , 87 , 88 , 89 , 90 , 91 , 92 , 93 , 94 , 95 , 96 , 97 , 98 ].…”