Blood-brain barrier opening with focused ultrasound in Parkinson\u2019s disease dementia

Carmen Gasca-Salas,Marta Del Álamo,José A Obeso,David Mata,Raúl Martínez-Fernández,Itay Rachmilevitch,Ignacio Obeso,Carlos Ordás-Bandera,J Ignacio Montero-Roblas,Frida Hernández-Fernández,Guglielmo Foffani,José A Pineda-Pardo,Beatriz Fernández-Rodríguez,Rafael Rodríguez-Rojas,Pasqualina Guida

doi:10.1038/s41467-021-21022-9

Abstract

MR-guided focused ultrasound (MRgFUS), in combination with intravenous microbubble administration, has been applied for focal temporary BBB opening in patients with neurodegenerative disorders and brain tumors. MRgFUS could become a therapeutic tool for drug delivery of putative neurorestorative therapies. Treatment for Parkinson’s disease with dementia (PDD) is an important unmet need. We initiated a prospective, single-arm, non-randomized, proof-of-concept, safety and feasibility phase I clinical trial (NCT03608553), which is still in progress. The primary outcomes of the study were to demonstrate the safety, feasibility and reversibility of BBB disruption in PDD, targeting the right parieto-occipito-temporal cortex where cortical pathology is foremost in this clinical state. Changes in β-amyloid burden, brain metabolism after treatments and neuropsychological assessments, were analyzed as exploratory measurements. Five patients were recruited from October 2018 until May 2019, and received two treatment sessions separated by 2–3 weeks. The results are set out in a descriptive manner. Overall, this procedure was feasible and reversible with no serious clinical or radiological side effects. We report BBB opening in the parieto-occipito-temporal junction in 8/10 treatments in 5 patients as demonstrated by gadolinium enhancement. In all cases the procedures were uneventful and no side effects were encountered associated with BBB opening. From pre- to post-treatment, mild cognitive improvement was observed, and no major changes were detected in amyloid or fluorodeoxyglucose PET. MRgFUS-BBB opening in PDD is thus safe, reversible, and can be performed repeatedly. This study provides encouragement for the concept of BBB opening for drug delivery to treat dementia in PD and other neurodegenerative disorders.

Highlights

MR-guided focused ultrasound (MRgFUS), in combination with intravenous microbubble administration, has been applied for focal temporary blood–brain barrier (BBB) opening in patients with neurodegenerative disorders and brain tumors
Postsonication gadolinium enhancement progressively disappeared within 24 h of BBB opening in 5 of the 10 procedures and within the following week in three procedures (Fig. 3)
In all cases the procedures were uneventful and no side effects were encountered associated with BBB opening

Summary

Introduction

MR-guided focused ultrasound (MRgFUS), in combination with intravenous microbubble administration, has been applied for focal temporary BBB opening in patients with neurodegenerative disorders and brain tumors. The primary outcomes of the study were to demonstrate the safety, feasibility and reversibility of BBB disruption in PDD, targeting the right parieto-occipitotemporal cortex where cortical pathology is foremost in this clinical state. MRgFUS in combination with intravenously injected microbubbles can temporarily open the BBB at specific brain targets[8]. This could allow delivery of drugs directly to the brain, paving the way for disease-modifying therapies[9]. FUS-BBB opening per se has resulted in significant reductions in brain pathology and memory improvement in the amyloid AD transgenic mouse model[10,11] as well as after delivery of antibodies against beta-amyloid[12], and tau[13]. We find that BBB can be safely, repeatedly, and temporarily opened in patients with PDD in the right parieto-occipitotemporal cortex

Methods

Results

Conclusion