A Study to Evaluate Temporary Blood Brain Barrier Disruption in Patients With Parkinson's Disease Dementia

This study is a prospective, single-arm, non-randomized, safety and feasibility trial of focal BBB disruption using the ExAblate® Model 4000 Type 2 (220 kHz) system with Luminity® ultrasound contrast in 10 patients with mild to moderate Parkinson's Disease Dementia. Patients, together with their caregivers, will be approached after their identification by a team of neurosurgeons and neurologists who specialize in the management of cognitive disorders and functional neurosurgery. The study will be discussed with them, and all patients, or their legal representatives will provide informed consent to participate in the study.

This first in human trial will be divided into two stages. In the first stage, patients will undergo small volume BBB disruption, establishing the minimum required sonication parameters to open the BBB, as evidenced by gadolinium enhancement on T1-weighted MRI. Stage I is defined as a discrete region of approximately 9 mm x 9 mm area in the right parietooccipitotemporal cortex. Multiple sonications will be performed starting at low energy and ramping up until the BBB is observed to open.

The subjects will then be removed from the ExAblate® Neuro device and followed for safety for 2 weeks. If the subject experienced BBB disruption without any serious adverse effects (such as brain edema), then the subject may proceed to Stage II where a larger volume (2.5-3.0 cm) will be targeted. Subjects will be followed for an additional 2 weeks for safety and preliminary effectiveness.

The staged approach will allow determination of:

• Safety of BBB disruption
• Feasibility of disruption the BBB
• Reversibility of BBB disruption
• Reproducibility of BBB disruption

Primary Inclusion Criteria:

• Parkinson´s Disease, according to the UK Parkinson´s Disease Society Brain Bank (Gelb et al. 1999)
• Parkinson´s Disease patients diagnosed with mild-moderate dementia according to the Movement Disorders Criteria (Emre et al. 2007)
• Able and willing to give informed consent, or has delegated this to a substitute decision maker.
• Mini Mental State Exam (MMSE) scores ≥16 (able to complete a Neuropsychological evaluation)
• Geriatric Depression Scale (GDS) score of ≤ 20
• Age: 60-80 years
• Able to attend all study visits (i.e., life expectancy of 1 year).

Primary Exclusion Criteria:

• Clips or other metallic implanted objects in the skull or the brain, except shunts
• Significant cardiac disease or unstable hemodynamic status
• Uncontrolled hypertension (systolic > 150 and diastolic BP > 100 on medication)
• Medications known to increase risk of hemorrhage, (e.g.: patients should be off of ASA for at least 7 days prior to treatment) or anticoagulants
• History of a bleeding disorder
• Significant depression and at potential risk of suicide
• Known sensitivity/allergy to gadolinium
• Any contraindications to MRI scanning
• History of seizure disorder or epilepsy
• History of drug or alcohol use disorder who may be at higher risk for seizure, infection, or poor executive functioning
• Chronic breathing disorders