Objective: To evaluate clinical safety, feasibility, and tissue penetration (by ¹⁸F-Choline PET) of MR-guided focused ultrasound (MRgFUS) blood-brain barrier opening (BBB-O) of the substantia nigra (SN) in Parkinson´s disease (PD) patients.

Background: The BBB is a major limiting factor for brain delivery of therapeutic investigational agents. The nigrostriatal system is especially vulnerable to neurodegeneration in PD. MRgFUS in combination with intravenous microbubble administration leads to focal temporary BBB-O. We have shown that striatal BBB-O of the parietal cortex and the putamen is viable in PD with cognitive impairment (Gasca-Salas et al, 2021; Pineda-Pardo et al 2022).

Method: Safety and feasibility study of BBB-O of the SN in PD (NCT03608553 trial). Patients underwent clinical evaluations and brain MR imaging with gadolinium at baseline, 24 hours, 14 days, and 3 months post-procedure. Gadolinium uptake is standardized  test for BBB-O. Three PD patients underwent MRgFUS for midbrain and putamen BBB-O. In two patients the procedure was repeated twice 3 weeks apart. In 2 patients ¹⁸F-Choline PET was performed immediately after BBB-O.

Results: The right SN was opened in 4 sessions in 3 patients, and the left SN in one patient once only.  The right SN and putamen were simultaneously opened unilaterally in 2 patients. No clinical or neuroimaging adverse events developed immediately or subsequently in any patient. 18F-Choline PET uptake in the midbrain SN region and the putamen was clearly enhanced precisely and exclusively in the targeted regions.

Conclusion: These findings indicate that nigrostriatal BBB opening of the nigro-striatal system by low intensity MRgFUS in PD is a feasible and well-tolerated approach.  18F-Choline PET reveals cell membrane binding, indirectly indicating penetration into the parenchyma after BBB-O. This minimally invasive technique could effectively facilitate delivery of putative neurorestorative molecules to brain regions vulnerable to neurodegeneration.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/substantia-nigra-blood-brain-barrier-opening-in-parkinsons-disease-pet-18f-choline-evidence-of-parenchymal-penetration/