Clinical trial NCT04118764: Non-invasive Blood-brain Barrier Opening in Alzheimer's Disease Patients Using Focused Ultrasound
Official title: Neuronavigation-guided Focused Ultrasound-induced Blood-brain Barrier Opening in Alzheimer's Disease Patients
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Alzheimer Disease
Keywords: focused ultrasound
blood-brain barrier opening
non-invasive therapy
Lead sponsor: Columbia University
Sponsor class: OTHER
Collaborators: name: National Institute on Aging (NIA)
First posted: 2019-10-08
Enrollment: 6
Sex: ALL
Minimum age (years): 50
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: DEVICE_FEASIBILITY

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: 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:

  * Probable MCI or AD consistent with criteria outlined in (McKhann et al 2011, Petersen et al 2018).
  * Mini Mental State Examination (MMSE) score between 12 and 26.
  * Modified Hachinski Ischemia Scale (MHIS) score of \<= 4
  * Short form Geriatric Depression Scale (GDS) score of \<= 6.
  * PET scan confirming amyloid plaque load using Amyvid (18F-Florbetapir).
* Ability to provide informed consent.

Exclusion Criteria:

* Contraindication for Magnetic Resonance Imaging (MRI).
* Contra-indication history or hypersensitivity to MRI contrast agents (e.g., Dotarem) or microbubbles (e.g., Definity).
* Prior brain surgery, including deep brain stimulation.
* Metallic implants.
* Moderate or severe uncontrolled hypertension (systolic blood pressure \> 140 mmHg).
* Abnormal coagulation profile, e.g. hemophilia A or B.
* Coagulopathy or under anticoagulant therapy.
* History of stroke or cardiovascular disease.
* Active/detectable gingivitis, herpes simplex, hepatitis, tuberculosis, and minor skin or respiratory infections.
* History of seizure disorder.
* History of asthma or allergies to food or medication with significant symptoms in past 3 years.
* Severe brain atrophy.
* Inability to comply with the procedures of the protocol, including follow-up MRI scans.
* Pregnancy or lactation.
* Impaired renal function with estimated glomerular filtration rate (eGFR) \<30 mL/min/1.73m2 provided by a standard blood test at maximum 2 weeks prior to the ultrasound treatment.
* Active infection/inflammation.
* Acute or chronic hemorrhages, i.e. \> 4 lobar microbleeds, and no siderosis or macrohemorrhages.
* Tumors or space occupying lesions.
* Meningeal enhancements.
* Intracranial hypotension.

Primary outcomes:
measure: Total Number of Individuals With Successful Opening of the BBB
timeFrame: Baseline through 3 days post-treatment
measure: Total Number of Safety Events Related to Opening of BBB
timeFrame: Baseline through 3 days post-treatment
Secondary outcomes:
measure: Percent Change in Amyloid PET Signal Intensity
timeFrame: Screening through 3 weeks post-treatment
measure: Change in Mini-Mental State Examination (MMSE) Score
timeFrame: Screening through 3 months post-treatment
Other outcomes:
Locations:
city: New York
country: United States
facility: Columbia University Irving Medical Center/NYPH
state: New York
Study officials:
affiliation: Columbia University
name: Elisa Konofagou, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.