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

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

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.

Conflict of interest statement

JAO has attended board meetings of Insightec and received an honorarium. RMF received honoraria for lecturing and payment to attend scientific meetings from Insightec. The other authors declare no competing interests.

Figures

Fig. 1. Flow chart illustrating patients screened…
Fig. 1. Flow chart illustrating patients screened and enrolled in the study.
CT computerized tomography, MMSE Mini-Mental State Exam, MR magnetic resonance.
Fig. 2. Gadolinium-enhanced T1-weighted images: blood–brain barrier…
Fig. 2. Gadolinium-enhanced T1-weighted images: blood–brain barrier opening.
Post: Blood–brain barrier opening of patient 2 in the targeted area immediately after sonication. 24 h: Same targeted area of patient 2, 24 h after treatment, without recognizable BBB opening. Top and bottom panels, respectively, show axial and coronal views of the parieto-occipito-temporal region.
Fig. 3. Gadolinium enhancement in T1-weighted.
Fig. 3. Gadolinium enhancement in T1-weighted.
Immediately after the blood–brain barrier (BBB) opening procedure in patients 1–4 (BBB01). The BBB opening was closed after 24 h (stage 1) in patients 1, 3, and 4 (BBB01-24 h) and in patient 2 at the 7th day MR follow-up (BBB01-7d). For stage 2 treatment, BBB was closed in patients 1 and 2 and in the following MRI study in patients 3 and 4 (BBB02-7d).
Fig. 4. Chronogram of the study investigations…
Fig. 4. Chronogram of the study investigations and procedures.
Tx treatment, Gad gadolinium, MRI magnetic resonance imaging, PET positron emission tomography, w weeks.

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Source: PubMed

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