Poster Abstracts
Patricia Junquera, MD
Interim Chair, Vice chair of clinical Services, Director of Multidisciplinary Edu
Florida International University/ Department of Psychiatry and Behavioral Health
Doral, Florida
Over the last 10-15 years, researchers have developed the Exablate 4000 Type 2 device that uses MR-guided focused ultrasound system (MRgFUS) to temporarily disrupt the blood-brain barrier (BBB) without any drilling or cutting. Ultrasound waves are sound waves at a frequency much higher than what we can hear. These ultrasound waves can be focused to a few millimeters precision. When Exablate is used with an ultrasound contrast agent (microscopic bubbles), the energy can be directed to a small targeted region and temporarily disrupts the blood-brain barrier. This process is non-invasive, temporary (for a few hours), controlled, and can be targeted
to specific diseased locations in the brain. When tested in animals, the disease pathology (Alzheimer plaque burden) was reduced and the animals improved their function.
The study is a multi-center study that uses low-intensity focused ultrasound (LIFU) to disrupt brain changes that lead to the neuron damage that causes memory and cognitive problems in patients.
An evaluation at the psychiatrist or neuro psychiatrist office will be performed to determine that a patient’s dementia is caused by Alzheimer’s and not due to other causes.
The evaluation includes a battery of scales and can take several hours. A caretaker or family member must also be present.
Next, the patient is seen at the Hospital where the MR Low frequency device is at, the Neurosurgeon team performs additional medical and imaging tests.
If the patient meets study inclusion criteria, study participation begins with the affixing of a stereotactic frame to the scalp under local anesthesia. Using MRI guidance, the ultrasound waves are directed to pre-determined areas of the brain. Patients are observed for several hours and are also seen the next day. The study involves three treatments, two weeks apart. After each session and at checkpoints along the way, patients will repeat imaging and psychological testing.
Purpose/Objectives: This is an early stage study in which MRI guided focused ultrasound is being tested in the brains of people with Alzheimer’s disease. In this study, patients who qualify will have an Exablate BBBD procedure which will be repeated at two and four weeks later for a total of 3 procedures over a 4-week period of time at Baptist Hospital of Miami. The purpose of temporarily and repeatedly disrupting the BBB is to allow factors within your blood circulatory system to cross over into the brain cells where amyloid (a large molecule associated with causing the disease) accumulates. It is hoped that the factors already in your bloodstream will be able to clear some of the amyloid out of those cells and allow your memory and/or cognition to improve. We hope that focused ultrasound may be a potential disease modifying treatment for Alzheimer’s disease.
During this procedure, the BBB disruption will be facilitated with the use of an ultrasound contrast agent that will be used in an investigational/experimental way (to create controlled oscillation of the microbubble resulting in BBB disruption), differently from that for which it was approved (visualization of the heart during heart surgery).
Methods: The Insightec Focused Ultrasound Platform Technology
Helmet-like device integrated into a standard MRI suite
Uses sound waves (ultrasound) produced by 1024 precisely focused transducer elements
Delivers therapeutic doses of energy through the intact skull, that converges at targeted tissue with submillimeter accuracy, deep inside the brain
Contrast agent Gadavist is used to aid in visualization of brain tissues for staging disease.
Confirms outcomes using real time acoustic and MR feedback
Multiple scales to determine the diagnosis of Alzheimer’s Dementia :MMSE, Geriatric Depression Scale (GDS), Alzheimer’s Disease Assessment Scale-cognitive (ADAS-Cog), NPI-Q, and Alzheimer’s Disease Cooperative Study Activity of Daily Living Scale (ADCS-ADL). FUS-mediated BBB opening in preclinical models has been found to promote amyloid-beta clearance, delivery of endogenous antibodies, activation of microglia (8, 12), and potential modulation of the glymphatic system (13). The significance with respect to human translation of amyloid reduction observed in animal models with FUS-mediated BBB disruption is unknown. However, FUS provides a noninvasive method for time-limited, precise, and large BBB opening, providing an exciting opportunity for research coupling FUS with targeted delivery of medications, immunotherapy, gene therapy, or stem cells into various complex and deep brain structures, including the hippocampus.
Results: The Current Phase II study industry sponsored is on-going with about 25 participants and continues to screen and enroll. The results in this study cannot be discussed.
There was a smaller pilot study in which results are available and are exciting.
Six participants (five female and one male: ages 55 y to 73 y) with early AD were enrolled at the West Virginia University Rockefeller Neuroscience Institute (n = 4) and Weill Cornell Medical College (n = 2). FUS treatment with up to five targets of either the right (n = 2) or left (n = 4) hippocampus/EC was performed. A total of 17 treatment sessions have been completed.
All participants tolerated the FUS procedure well and were discharged home within 24 h. There were no treatment-related adverse effects or neurological changes (up to 15 mo post-FUS). Formal cognitive assessments at 30 d after the last treatment in the first five subjects showed no clinically meaningful changes. T2* MRI following FUS treatment and at subsequent follow-up did not indicate overt hemorrhage. MRI with gadobutrol IV contrast post-FUS treatment revealed immediate hippocampal parenchymal enhancement at the target region in all 17 treatment sessions, indicating enhanced BBB permeability, with no off-target enhancement. This parenchymal contrast enhancement resolved within 24 h after FUS treatment. MRI-based volumetric analysis of BBB opening in the hippocampus demonstrated parenchymal contrast enhancement of 95 ± 4% of the FUS targeted volume, ranging from 318 mm3 (two targets) to 873 mm3 (five targets). This BBB opening corresponds to 14 to 71% (average 29%) of the overall hippocampus volume given the variation in anatomy, hippocampal atrophy, dosing, and number of targets.
Conclusions: In summary, an ongoing multicenter phase II trial demonstrating that a large volume of the BBB in the deep structure of the hippocampus and EC can be safely, reversibly, and repeatedly opened with spatial precision. The noninvasive, on-demand feature of FUS technology and focal BBB opening offers a unique opportunity for targeted delivery of therapeutics to meaningful volumes of essential brain structures in AD and other neurological conditions.
References: 1. N. Lipsman et al., Blood-brain barrier opening in Alzheimer’s disease using MR-guided focused ultrasound. Nat. Commun. 9, 2336 (2018).
2. G. M. McKhann et al., The diagnosis of dementia due to Alzheimer’s disease: Recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement. 7, 263–269 (2011).
3. Rezai, A.R.; Ranjan, M.; D’Haese, P.F.; Haut, M.W.; Carpenter, J.; Najib, U.; Mehta, R.I.; Chazen, J.L.; Zibly, Z.; Yates, J.R.; et al. Noninvasive hippocampal blood-brain barrier opening in Alzheimer’s disease with focused ultrasound. Proc. Natl. Acad. Sci. USA 2020, 117, 9180–9182.