The primary purpose of this phase 1b study is to further assess the safety and reversibility of focused ultrasound induced blood-brain barrier opening (FUS-BBBO) in participants with Alzheimer´s Disease (AD) using a single-element transducer with neuronavigation guidance. Preliminary results from our phase 1a study demonstrate that our neuronavigation-guided FUS system was capable of safely and transiently open the BBB in participants with AD. The information collected in this new study may be used to design future clinical trials to ultimately provide a viable alternative for treatment of AD in a safe and noninvasive manner.
Our secondary objective includes the assessment of the therapeutic efficacy of FUS-BBBO in reducing amyloid beta and neurofibrillary tangles, the main hallmark pathologies of AD, using PET tracers. Based on our preclinical studies in AD transgenic mouse models, FUS-BBBO alone was able to reduce both the amyloid beta and tau protein load, resulting in improvements in behavioral tasks assessing memory. Therefore, in this new study, the effect of FUS-BBBO on the amyloid beta and tau protein load in patients with AD will be assessed through the use of PET tracers.
Age greater than 50 years old.
MMSE score between 12 and 26.
Modified Hachinski Ischemia Scale (MHIS) score of <= 4
Short form Geriatric Depression Scale (GDS) score of <= 6.
Prior administration of any amyloid-reducing agent such as aducanumab or lecanemab.
Contraindication for MRI.
Contra-indication history or hypersensitivity to MRI contrast agents (e.g., Dotarem) or microbubbles (e.g., Definity, Lumason), including polyethylene glycol (PEG) allergy.
Prior brain surgery, including deep brain stimulation.
Single group
Neuronavigation-guided single-element focused ultrasound transducer
DeviceNon-invasive focused ultrasound-induced blood-brain barrier opening will be attempted using a single-element transducer, guided with a neuronavigation system.
Lumason
DrugNew packages of Lumason microbubbles will be shipped from Bracco Diagnostics Inc. and will be used in conjunction with the ultrasound transducer to temporarily open the BBB. Lumason microbubbles will be freshly activated before treatment sonication and will be drawn using a 10-ml syringe to reach the desired dosage of 0.1mL/kg right before the intravenous injection.
Magnetic Resonance Imaging (MRI) with or without gadolinium contrast agents
Other interventionA high-resolution MRI (with and without gadolinium (Dotarem) contrast agent) will be acquired prior to BBB opening on the GE SIGNATM Premier (3T) (same scanner as in the NHP study) for pre-treatment planning and screening purposes. Then, a second MRI (with and without gadolinium) will be acquired and read by a Board-Certified Radiologist immediately after the treatment sonication in order to assess the BBB opening and safety. Finally, a final follow-up MRI (with and without gadolinium) will be conducted 3 days (±1 day) after the treatment to confirm BBB closing and/or safety. This will be read by a Board-Certified Radiologist as well. All MRI procedures will be performed at the CUIMC/Neurological Institute of New York.
Positron Emission Tomography (PET)
RadiationA first PET/CT scan with Amyvid (18F-Florbetapir) and MK-6240 (F18-Florquinitau) tracers will be performed on the SIEMENS Biograph 64 to assess the baseline amyloid plaque load and tau load before the treatment, respectively. Finally, two follow-up PET/CT scans will be conducted 3 weeks (±1 week) and 3 months (±2 weeks) post-treatment to assess amyloid plaque load (using Amyvid) and tau load (using MK-6240).
Amyvid
DrugAmyloid PET tracer Amyvid (18F- Florbetapir) will be stored in their original container with proper radiation shielding at 25 °C and only handled by properly trained personnel in the handling and administration of radioactive materials, which requires employing proper radiation protection procedures.
MK-6240
Drug\[18F\]MK-6240 will be synthesized, purified, and formulated at the local radiochemistry synthesis laboratory and will be administered as a sterile, pyrogen-free solution by IV injection. The radiotracer \[18F\]MK-6240 is supplied in a sterile, ready-to-use solution, direct from the Columbia University PET Center. It is supplied for a targeted calibration time, the precise volume to be administered at a given time can be calculated based on the decay of F-18. Only personnel properly trained in the handling and administration of radioactive materials should handle \[18F\]MK-6240. Usual radiation protection procedures should be used for handling radiotracers, including shielding (lead or tungsten containers/shields), and personal protective equipment including gloves. There are no specific procedures required for the handling of \[18F\]MK-6240. The expiry of \[18F\]MK-6240 is eight hours from the time at End of Synthesis (EOS).
Dotarem
DrugFDA-approved medication. Dotarem will be handled in accordance with the CUMC Research Pharmacy procedures and NYP policy P168, Version 4. Dotarem will be used according to its labeling. 0.2 ml/kg.
Blood draw
Diagnostic testBlood samples will be collected through an intravenous catheter or a finger prick during screening, on the day of the FUS treatment and the follow up examinations (week 3 and month 3). These samples will be processed to assess any blood content changes induced by the focused ultrasound treatment.
UR5e
DeviceUniversal Robots robotic arm used for the accurate positioning of the neuronavigation-guided single-element focused ultrasound transducer with respect to the patient's head.
Urine test
Diagnostic testUrine test required following the MRI and PET Centers policy used clinically for pregnancy screening
Total Number of Individuals With Successful Opening of the BBB
Opening the BBB successfully in all the patients, while obtaining a volume of BBB opened being similar and consistent for all patients
Total Number of Safety Events Related to Opening of BBB
Showing safe BBB opening for all patients without any Adverse Event nor Serious Adverse Event, and showing its safety as well in 3 days after treatment
Percent Change in Amyloid PET Signal Intensity
A moderately shown in our previous clinical trial study, we expect to observe a slowed down increase of Amyloid protein load after the treatment on the two follow-ups performed at 3 weeks (±1 week) and 3 months (±2 week) after treatment.
Percent Change in MK-6240 PET Signal Intensity
As shown in our previous studies in mice, we expect to observe a slowed down increase or reduction on Tau protein load after the treatment on the two follow-ups performed at 3 weeks (±1 week) and 3 months (±2 week) after treatment.
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