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The blood–brain barrier (BBB) protects the brain but is also an important obstacle for the effective delivery of therapeutics in Alzheimer’s disease and other neurodegenerative disorders. Transcranial magnetic resonance-guided focused ultrasound (MRgFUS) has been shown to reversibly disrupt the BBB. However, treatment of diffuse regions across the brain along with the effect on Alzheimer’s disease relevant pathology need to be better characterized. This study is an open-labelled single-arm trial (NCT03739905) to investigate the feasibility of modulating BBB permeability in the default mode network and the impact on cognition, amyloid and tau pathology as well as BBB integrity. Nine participants [mean age 70.2 ± 7.2 years, mean Mini-Mental State Examination (MMSE) 21.9] underwent three biweekly procedures with follow-up visits up to 6 months. The BBB permeability of the bilateral hippocampi, anterior cingulate cortex and precuneus was transiently increased without grade 3 or higher adverse events. Participants did not experience worsening trajectory of cognitive decline (ADAS-cog11, MMSE). Whole brain vertex-based analysis of the 18F-florbetaben PET imaging demonstrated clusters of modest SUVR reduction in the right parahippocampal and inferior temporal lobe. However, CSF and blood biomarkers did not demonstrate any amelioration of Alzheimer’s disease pathology (P-tau181, amyloid-β42/40 ratio), nor did it show persistent BBB dysfunction (plasma PDGFRbeta and CSF-to-plasma albumin ratio). This study provides neuroimaging and fluid biomarker data to characterize the safety profile of MRgFUS BBB modulation in neurodegeneration as a potential strategy for enhanced therapeutic delivery.

GBA1 mutation is the most common genetic risk factor for Parkinson's disease (PD). Replacement of the lysosomal enzyme glucocerebrosidase (GCase) slows neurodegeneration in PD models and may be a promising disease-modifying therapy in patients with PD. However, recombinant GCase has limited penetration through the blood-brain barrier (BBB). Microbubble-mediated magnetic resonance-guided focused ultrasound (MRgFUS) can reversibly disrupt the BBB for drug delivery.This open-label phase I study investigated the safety and feasibility of MRgFUS putaminal delivery of intravenous GCase at escalating doses (15 to 30 to 60 IU/kg) every 2 weeks in four patients with PD with GBA1 mutations.BBB permeability was achieved and restored in all patients as quantified by dynamic contrast-enhanced magnetic resonance imaging after treatment. There were no serious adverse events. Two patients developed transient dyskinesia after treatment. Blinded Movement Disorder Society-Unified Parkinson's Disease Rating Scale motor scores off medication decreased by 12% at 6 months from baseline (from 26 ± 9 to 22 ± 6). Standardized uptake value ratio on fluorodeoxyglucose positron emission tomography imaging in the treated putamen reduced from 1.66 ± 0.14 to 1.27 ± 0.08.Results from this study demonstrate the safety and feasibility of MRgFUS GCase delivery in PD and support further investigation of this approach. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Background Liquid biopsy is promising for early detection, monitoring of response, and recurrence of cancer. The blood-brain barrier (BBB) limits the shedding of biomarker, such as cell-free DNA (cfDNA), into the blood from brain tumors, and their detection by conventional assays. Transcranial MR-guided focused ultrasound (MRgFUS) can safely and transiently open the BBB, providing an opportunity for less-invasive access to brain pathology. We hypothesized that MRgFUS can enrich the signal of circulating brain-derived biomarkers to aid in liquid biopsy. Methods Nine patients were treated in a prospective single-arm, open-label trial to investigate serial MRgFUS and adjuvant temozolomide combination in patients with glioblastoma (NCT03616860). Blood samples were collected as an exploratory measure within the hours before and after sonication, with control samples from non-brain tumor patients undergoing BBB opening (BBBO) alone (NCT03739905). Results Brain regions averaging 7.8 ± 6.0 cm3 (range 0.8-23.1 cm3) were successfully treated within 111 ± 39 minutes without any serious adverse events. We found MRgFUS acutely enhanced plasma cfDNA (2.6 ± 1.2-fold, P < .01, Wilcoxon signed-rank test), neuron-derived extracellular vesicles (3.2 ± 1.9-fold, P < .01), and brain-specific protein S100b (1.4 ± 0.2-fold, P < .01). Further comparison of the cfDNA methylation profiles suggests a signature that is disease- and post-BBBO-specific, in keeping with our hypothesis. We also found cfDNA-mutant copies of isocitrate dehydrogenase 1 (IDH1) increased, although this was in only one patient known to harbor the tumor mutation. Conclusions This first-in-human proof-of-concept study shows MRgFUS enriches the signal of circulating brain-derived biomarkers, demonstrating the potential of the technology to support liquid biopsy for the brain.

OBJECTIVE The development of transcranial MR-guided focused ultrasound (MRgFUS) has revitalized the practice of lesioning procedures in functional neurosurgery. Previous health economic analysis found MRgFUS thalamotomy to be a cost-effective treatment for patients with essential tremor, supporting its reimbursement. With the publication of level I evidence in support of MRgFUS thalamotomy for patients with tremor-dominant Parkinson’s disease (TDPD), the authors performed a health economic comparison between MRgFUS, deep brain stimulation (DBS), and medical therapy. METHODS The authors used a decision tree model with rollback analysis and one-factor sensitivity analysis. Literature searches of MRgFUS thalamotomy and unilateral DBS of the ventrointermediate nucleus of the thalamus for TDPD were performed to determine the utility and probabilities for the model. Costs in Canadian dollars (CAD) were derived from the Schedule of Benefits and Fees in Ontario, Canada, and expert opinion on usage. RESULTS MRgFUS was associated with an expected cost of $14,831 CAD. Adding MRgFUS to continued medical therapy resulted in an incremental cost-effectiveness ratio of $30,078 per quality-adjusted life year (QALY), which remained cost-effective under various scenarios in the sensitivity analysis. Comparing DBS to MRgFUS, while DBS did not achieve the willingness-to-pay threshold ($56,503 per QALY) in the base case scenario, it did so under several scenarios in the sensitivity analysis. CONCLUSIONS MRgFUS thalamotomy is a cost-effective treatment for patients with TDPD, particularly over continued medical therapy. While MRgFUS remains competitive with DBS, the cost-effectiveness advantage is less substantial. These results will help inform the integration of this technology in the healthcare system.

Transcranial MR-guided focused ultrasound (MRgFUS) is a rapidly developing technology in neuroscience for manipulating brain structure and function without open surgery. The effectiveness of transcranial MRgFUS for thermoablation is well established, and the technique is actively employed worldwide for movement disorders including essential tremor. A growing number of centers are also investigating the potential of microbubble-mediated focused ultrasound-induced opening of the blood-brain barrier (BBB) for targeted drug delivery to the brain. Here, we provide a technical overview of the principles, clinical workflow, and operator considerations of transcranial MRgFUS procedures for both thermoablation and BBB opening.