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| ID | Type | Description | Link |
|---|---|---|---|
| R01AG038961 | U.S. NIH Grant/Contract | View source |
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| Name | Class |
|---|---|
| National Institute on Aging (NIA) | NIH |
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The purpose of this study is to test a new technique that may, in the future, help deliver medications to the brain of people with Alzheimer's disease. Participants in this study will undergo a focused ultrasound treatment to the brain, along with Magnetic Resonance Imagine (MRI) and Positron Emission Tomography (PET) scans.
Central nervous system disorders are currently being symptomatically treated since the molecular events provoking their onset have not been yet identified. Drug delivery techniques have to overcome the almost impermeable blood-brain barrier (BBB) and can be grouped into two main categories: (i) invasive and targeted, and (ii) non-invasive and non-targeted methods. However, the technological advances of the past decades revealed the immense potential of focused ultrasound (FUS) in transcranial applications. In contrast to other techniques, FUS-mediated BBB opening is both non-invasive and targeted. The localized energy delivery coupled with the circulation of intravenously administered microbubbles initiates biological effects confined only to the vessel walls and contained only in the targeted region within the brain.
The purpose of the study is to assess the safety and feasibility of focused ultrasound-induced blood-brain barrier opening in Alzheimer's disease patients, using a single-element transducer with neuronavigation guidance. The investigators will also test whether treatment with focused ultrasound alone alters the amyloid protein levels in the treated brain areas and its potential effects on the cognitive function of Alzheimer's patients.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Focused ultrasound treatment | Experimental | Neuronavigation-guided focused ultrasound treatment in Alzheimer's disease patients using a single-element transducer in conjunction with Definity Microbubbles (10 μl/kg). |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Neuronavigation-guided single-element focused ultrasound transducer | Device | Non-invasive focused ultrasound-induced blood-brain barrier opening will be attempted using a single-element transducer, guided with a neuronavigation system. |
| Measure | Description | Time Frame |
|---|---|---|
| Total Number of Individuals With Successful Opening of the BBB | The total number of individuals with successful opening of the BBB will be assessed. Blood-brain barrier opening volume will be measured in mm^3 through contrast-enhanced T1-weighted MRI on the day of the focused ultrasound treatment and 3 days after treatment, to confirm blood-brain barrier restoration. | Baseline through 3 days post-treatment |
| Total Number of Safety Events Related to Opening of BBB | The total number of safety events related to opening of the BBB as assessed by T2 and susceptibility-weighted (SWI) MRI. Safety will be established by the presence and the total area of hyper-intense or hypo-intense areas in the T2 and SWI scans. | Baseline through 3 days post-treatment |
| Measure | Description | Time Frame |
|---|---|---|
| Percent Change in Amyloid PET Signal Intensity | Amyloid plaques will be assessed through PET imaging before and after the focused ultrasound treatment. The standardized uptake value ratio images (SUVr) will be compared before and after the FUS treatment, to investigate if there is a change in the uptake of 18F-Florbetapir within the treated area. | Screening through 3 weeks post-treatment |
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Inclusion Criteria:
50 years of age or older.
Diagnosis of early Alzheimer's disease (AD) or mild cognitive impairment (MCI) at minimum. All following criteria must be met:
Ability to provide informed consent.
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Elisa Konofagou, PhD | Columbia University | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Columbia University Irving Medical Center/NYPH | New York | New York | 11021 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 29789530 | Background | Wu SY, Aurup C, Sanchez CS, Grondin J, Zheng W, Kamimura H, Ferrera VP, Konofagou EE. Efficient Blood-Brain Barrier Opening in Primates with Neuronavigation-Guided Ultrasound and Real-Time Acoustic Mapping. Sci Rep. 2018 May 22;8(1):7978. doi: 10.1038/s41598-018-25904-9. | |
| 31668690 | Background | Pouliopoulos AN, Wu SY, Burgess MT, Karakatsani ME, Kamimura HAS, Konofagou EE. A Clinical System for Non-invasive Blood-Brain Barrier Opening Using a Neuronavigation-Guided Single-Element Focused Ultrasound Transducer. Ultrasound Med Biol. 2020 Jan;46(1):73-89. doi: 10.1016/j.ultrasmedbio.2019.09.010. Epub 2019 Oct 25. |
| Label | URL |
|---|---|
| Ultrasound Elasticity Imaging Laboratory - Columbia University | View source |
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No individual participant data (IPD) will be shared with other researchers.
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| ID | Title | Description |
|---|---|---|
| FG000 | Focused Ultrasound Treatment | Neuronavigation-guided focused ultrasound treatment in Alzheimer's disease patients using a single-element transducer in conjunction with Definity Microbubbles (10 μl/kg). Neuronavigation-guided single-element focused ultrasound transducer: Non-invasive focused ultrasound-induced blood-brain barrier opening will be attempted using a single-element transducer, guided with a neuronavigation system. Definity: Definity microbubbles (10 μl/kg) will be used in conjunction with the ultrasound transducer to temporarily open the blood brain barrier. Magnetic Resonance Imaging (MRI) with or without gadolinium contrast agents: MRI scans will be completed at baseline and immediately after the focused ultrasound treatment to confirm BBB opening and safety. A follow-up MRI will be performed three days after treatment to confirm BBB closure, only in the case of successful BBB opening. Positron Emission Tomography (PET): A follow-up PET scan will be performed three days after treatment to determine amyloid plaque load. Amyvid: To be used during the PET scan to determine uptake of Amyvid within the treated area. |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Overall Study |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Dec 6, 2022 |
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| Definity | Drug | Definity microbubbles (10 μl/kg) will be used in conjunction with the ultrasound transducer to temporarily open the blood brain barrier. |
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| Magnetic Resonance Imaging (MRI) with or without gadolinium contrast agents | Other | MRI scans will be completed at baseline and immediately after the focused ultrasound treatment to confirm BBB opening and safety. A follow-up MRI will be performed three days after treatment to confirm BBB closure, only in the case of successful BBB opening. |
|
| Positron Emission Tomography (PET) | Other | A follow-up PET scan will be performed three days after treatment to determine amyloid plaque load. |
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| Amyvid | Other | To be used during the PET scan to determine uptake of Amyvid within the treated area. |
|
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| Change in Mini-Mental State Examination (MMSE) Score | The MMSE is a questionnaire that is used to measure cognitive impairment. The total score range is 0 to 30, with a higher score indicating a better outcome. Cognitive function will be assessed before and after the focused ultrasound treatment to determine the change in MMSE. | Screening through 3 months post-treatment |
| 37554284 | Derived | Karakatsani ME, Ji R, Murillo MF, Kugelman T, Kwon N, Lao YH, Liu K, Pouliopoulos AN, Honig LS, Duff KE, Konofagou EE. Focused ultrasound mitigates pathology and improves spatial memory in Alzheimer's mice and patients. Theranostics. 2023 Jul 14;13(12):4102-4120. doi: 10.7150/thno.79898. eCollection 2023. |
| 34815790 | Derived | Mathew AS, Gorick CM, Price RJ. Multiple regression analysis of a comprehensive transcriptomic data assembly elucidates mechanically- and biochemically-driven responses to focused ultrasound blood-brain barrier disruption. Theranostics. 2021 Oct 11;11(20):9847-9858. doi: 10.7150/thno.65064. eCollection 2021. |
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| NOT COMPLETED |
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| ID | Title | Description |
|---|---|---|
| BG000 | Focused Ultrasound Treatment | Neuronavigation-guided focused ultrasound treatment in Alzheimer's disease patients using a single-element transducer in conjunction with Definity Microbubbles (10 μl/kg). Neuronavigation-guided single-element focused ultrasound transducer: Non-invasive focused ultrasound-induced blood-brain barrier opening will be attempted using a single-element transducer, guided with a neuronavigation system. Definity: Definity microbubbles (10 μl/kg) will be used in conjunction with the ultrasound transducer to temporarily open the blood brain barrier. Magnetic Resonance Imaging (MRI) with or without gadolinium contrast agents: MRI scans will be completed at baseline and immediately after the focused ultrasound treatment to confirm BBB opening and safety. A follow-up MRI will be performed three days after treatment to confirm BBB closure, only in the case of successful BBB opening. Positron Emission Tomography (PET): A follow-up PET scan will be performed three days after treatment to determine amyloid plaque load. Amyvid: To be used during the PET scan to determine uptake of Amyvid within the treated area. |
| Units | Counts |
|---|---|
| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean | Standard Deviation | years |
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| Sex: Female, Male | Count of Participants | Participants |
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| Ethnicity (NIH/OMB) | Count of Participants | Participants |
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| Race (NIH/OMB) | Count of Participants | Participants |
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| MMSE | The MMSE is a questionnaire that is used to measure cognitive impairment. The total score range is 0 to 30, with a higher score indicating a better outcome. | Mean | Standard Deviation | score on a scale |
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| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Total Number of Individuals With Successful Opening of the BBB | The total number of individuals with successful opening of the BBB will be assessed. Blood-brain barrier opening volume will be measured in mm^3 through contrast-enhanced T1-weighted MRI on the day of the focused ultrasound treatment and 3 days after treatment, to confirm blood-brain barrier restoration. | Posted | Count of Participants | Participants | Baseline through 3 days post-treatment |
|
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| |||||||||||||||||||||||||||
| Primary | Total Number of Safety Events Related to Opening of BBB | The total number of safety events related to opening of the BBB as assessed by T2 and susceptibility-weighted (SWI) MRI. Safety will be established by the presence and the total area of hyper-intense or hypo-intense areas in the T2 and SWI scans. | Posted | Number | adverse events | Baseline through 3 days post-treatment |
| |||||||||||||||||||||||||||||
| Secondary | Percent Change in Amyloid PET Signal Intensity | Amyloid plaques will be assessed through PET imaging before and after the focused ultrasound treatment. The standardized uptake value ratio images (SUVr) will be compared before and after the FUS treatment, to investigate if there is a change in the uptake of 18F-Florbetapir within the treated area. | Posted | Mean | Standard Deviation | percent change | Screening through 3 weeks post-treatment |
| ||||||||||||||||||||||||||||
| Secondary | Change in Mini-Mental State Examination (MMSE) Score | The MMSE is a questionnaire that is used to measure cognitive impairment. The total score range is 0 to 30, with a higher score indicating a better outcome. Cognitive function will be assessed before and after the focused ultrasound treatment to determine the change in MMSE. | Posted | Mean | Standard Deviation | score on a scale | Screening through 3 months post-treatment |
|
Up to 5 months
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Focused Ultrasound Treatment | Neuronavigation-guided focused ultrasound treatment in Alzheimer's disease patients using a single-element transducer in conjunction with Definity Microbubbles (10 μl/kg). Neuronavigation-guided single-element focused ultrasound transducer: Non-invasive focused ultrasound-induced blood-brain barrier opening will be attempted using a single-element transducer, guided with a neuronavigation system. Definity: Definity microbubbles (10 μl/kg) will be used in conjunction with the ultrasound transducer to temporarily open the blood brain barrier. Magnetic Resonance Imaging (MRI) with or without gadolinium contrast agents: MRI scans will be completed at baseline and immediately after the focused ultrasound treatment to confirm BBB opening and safety. A follow-up MRI will be performed three days after treatment to confirm BBB closure, only in the case of successful BBB opening. Positron Emission Tomography (PET): A follow-up PET scan will be performed three days after treatment to determine amyloid plaque load. Amyvid: To be used during the PET scan to determine uptake of Amyvid within the treated area. | 0 | 6 | 0 | 6 | 1 | 6 |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Mild focal edema | Injury, poisoning and procedural complications | Systematic Assessment | Magnetic resonance imaging of one subject displayed a mild focal cortical and subcortical edema and superficial hemorrhage, likely meningeal. The subject was asymptomatic and the abnormalities resolved in the follow-up scans on day 15. |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Elisa Konofagou, PhD, Robert and Margaret Hariri Professor in Biomedical Engineering and Radiology | Columbia University | 212-342-0863 | ek2191@columbia.edu |
| May 9, 2024 |
| Prot_SAP_000.pdf |
| ID | Term |
|---|---|
| D000544 | Alzheimer Disease |
| ID | Term |
|---|---|
| D003704 | Dementia |
| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
| D009422 | Nervous System Diseases |
| D024801 | Tauopathies |
| D019636 | Neurodegenerative Diseases |
| D019965 | Neurocognitive Disorders |
| D001523 | Mental Disorders |
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| ID | Term |
|---|---|
| C042852 | perflutren |
| D009682 | Magnetic Resonance Spectroscopy |
| C545186 | florbetapir |
| ID | Term |
|---|---|
| D013057 | Spectrum Analysis |
| D002623 | Chemistry Techniques, Analytical |
| D008919 | Investigative Techniques |
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| Unknown or Not Reported |
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| Native Hawaiian or Other Pacific Islander |
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| Black or African American |
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| White |
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| More than one race |
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| Unknown or Not Reported |
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