Blood-brain barrier opening with focused ultrasound in Parkinson’s disease dementia

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.

Oncolytic Viro-Immunotherapy: An Emerging Option in the Treatment of Gliomas

“…Pre-clinical studies have demonstrated that low-intensity pulsed ultrasound in combination with systemically injected microbubbles could temporarily open the BBB in a localized manner (244). This concept is currently undergoing clinical trials, and has already demonstrated safety and tolerability in patients, and therefore may provide enhanced systemic OV delivery capabilities (245,246). For intratumoral delivery only, 1) the expense and complexity of neurosurgical procedures, limiting repeat administration.…”

Viral alpha-synuclein knockdown prevents spreading synucleinopathy

“… 25 The importance of this emerging technology is further underscored by successful Phase I clinical trials in Alzheimer’s disease and Parkinson’s disease patients that support the feasibility and safety of BBB opening with low intensity focal sonication. 100 , 101 With ongoing improvements to vector design and CNS delivery, combinatorial gene therapies targeting cell survival and α-syn may offer long-lasting benefits by specifically targeting affected neuronal pathways implicated by prodromal disease symptoms, and which could mitigate further transmission of synucleinopathy.…”

Focused Ultrasound Combined with Microbubbles in Central Nervous System Applications

“…Two sessions of FUS were given with an interval of 2–3 weeks and without side effects. There were mild cognitive improvements, but no major changes in amyloid plaques were detected using 18 F-FDG PET [ 110 , 111 ].…”