Feasibility Study of Transcranial Ultrasound Stimulation on Alzheimer's Disease Patients (TUS)

Currently, the main treatment method for Alzheimer's disease (AD) is chemotherapy. However, the effectiveness of drugs is moderate and there are several side effects. In this clinical trial, the investigators would like to activate the brain by the transcranial ultrasound stimulation (TUS). This is a feasibility study to evaluate the safety and initial effectiveness of TUS for the treatment of patients with mild AD.

Study Overview

• Status: Unknown
• Conditions: Alzheimer Disease
• Intervention / Treatment: Device: Transcranial Ultrasound Stimulation

Detailed Description

The purpose of this study is to verify the feasibility of low intensity transcranial ultrasound stimulation (TUS) for patients with mild Alzheimer's disease (AD). As a secondary aim, the investigators will explore whether the TUS is associated with improvement in cognitive functioning six and forty-six weeks following the intervention.

Subjects will be randomly assigned to one of two experimental groups which with or without the TUS administration.

The investigators will study up to 20 subjects with mild AD. Initially, subjects will undergo a screening assessment with a study physician to determine medical and psychiatric history, establish AD diagnosis, and undergo a bold draw. Subjects that meet criteria and agree to participate in the study will undergo a follow-up visit. In the baseline measurement visit, participants will first undergo neuropsychological testing. Participants will be randomly assigned to one of two groups. Participants will then be administrated TUS treatment for six weeks. Subsequently, participants will undergo a series of neuropsychological test. A final follow-up assessment will be administered at forty-six weeks.

• Study Type: Interventional
• Enrollment (Anticipated): 10
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Jong-Ling Fuh, M.D.; Phone Number: 886-2-28762522; Email: jlfuh@vghtpe.gov.tw
• Study Contact Backup: Name: Feng-Yi Yang, Ph.D.; Phone Number: 886-2-28267281; Email: fyyang@ym.edu.tw

Study Locations

• Taiwan
  • Taipei, Taiwan
    • Recruiting
    • Taipei Veterans General Hospital
    • Contact: Jong-Ling Fuh, M.D.
    • Principal Investigator: Jong-Li Fuh, M.D.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 53 years to 88 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Age between 55 and 90 years old
2. Weight greater than 50 kg
3. Male or Female
4. Good understanding of written and verbal Chinese
5. Geriatric Depression Scale (GDS) score of < 8
6. Mild AD patients (Mini-Mental State Examination (MMSE) 20-26)
7. Probable AD consistent with NIA/AA criteria
8. The blood flow of bilateral middle cerebral artery M1 can be detected by Transcranial Color Doppler (TCD)
9. Caregiver spending at least 10 hours per week with the patient
10. Agreement to obey the rules of this study
11. Use of cholinesterase inhibitors for AD (Aricept, Namenda, etc.) will be allowed as long as the participant has been on a stable dose for at least six months
12. Does have a reliable caregiver in frequent contact with the patient and can accompany the patient to the clinic and treatment

Exclusion Criteria:

1. Evidence of any other major neurologic or other physical illness that could produce cognitive deterioration, except for mild cognitive impairment (MCI) and any history of stroke or diabetes
2. History of myocardial infarction within the previous year or unstable cardiac disease
3. Any contraindications to MRI scanning such as metallic implants, claustrophibia or too large for MRI scanner
4. History of liver disease or severely impaired renal function
5. The blood flow of either unilateral middle cerebral artery M1 can't be detected by Transcranial Color Doppler (TCD)
6. Major psychiatric disorders, such as bipolar disorder or schizophrenia, or persons with current untreated major depression
7. Pregnant or breastfeeding women

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Device Feasibility
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: TUS treatment; AD patients with TUS treatment	Device: Transcranial Ultrasound Stimulation; TUS activate the brain cells
No Intervention: Non-TUS treatment; AD patients with Non-TUS treatment

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Device and procedure related adverse events recording	Rate of adverse events following each treatment through end of study Clinical and MRI evaluation	up to 46 weeks after treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog)	ADAS was designed to measure the severity of the most important symptoms of Alzheimer's disease (AD). Its subscale ADAS-cog is the most popular cognitive testing instrument used in clinical trials of nootropics. It consists of 11 tasks measuring the disturbances of memory, language, praxis, attention and other cognitive abilities which are often referred to as the core symptoms of AD. The test administrator adds up points for the errors in each task of the ADAS-Cog for a total score. Total scores range from 0-70. The greater the dysfunction, the greater the score.	Change from baseline at 7, 12, 24, and 52 week
Clinical Dementia Rating (CDR)	The Clinical Dementia Rating or CDR is a numeric scale used to quantify the severity of symptoms of dementia (i.e. its 'stage'). Using a structured-interview protocol, qualified health professional assesses a patient's cognitive and functional performance in six areas: memory, orientation, judgment & problem solving, community affairs, home & hobbies, and personal care. Scores in each of these are combined to obtain a composite score ranging from 0 through 3, with 0 meaning of no symptoms, 0.5 very mild dementia, 1 mild dementia, 2 moderate dementia and 3 severe dementia.	Change from baseline at 12 and 52 week
Neuropsychiatric Inventory Questionnaire (NPI-Q)	NPI-Q is a carer-based tool that assesses the possible presence of 12 symptoms in dementia cases, including delusions, hallucinations, agitation/aggression, dysphoria/depression, anxiety, euphoria/elation, apathy/indifference, disinhibition, irritability/lability, aberrant motor behaviors, night-time behavioral disturbances and appetite/eating disturbances. The severity scale has scores ranging from 1 to 3 points (1=mild; 2=moderate; and 3=severe) and the scale for assessing caregiver distress has scores ranging from 0 to 5 points (0=no distress; 1=minimal distress; 2=mild distress; 3=moderate distress; 4=severe distress; and 5=extreme distress). The total scores of severity and caregiver stress are summed of each 12 items separately, with with higher scores indicating a greater number of neuropsychiatric symptoms or distress.	Change from baseline at 12 and 52 week
Transcranial Doppler (TCD)	Cerebral blood flow evaluation	Changes in blood flow from baseline at 12 and 52 week
Magnetic Resonance Image (MRI)	Brain observation	Change from baseline at 12 and 52 week

Collaborators and Investigators

• Sponsor: National Yang Ming University
• Collaborators: Taipei Veterans General Hospital, Taiwan
• Investigators: Principal Investigator: Feng-Yi Yang, Ph.D., National Yang Ming University

Publications and helpful links

General Publications

• Chen TT, Lan TH, Yang FY. Low-Intensity Pulsed Ultrasound Attenuates LPS-Induced Neuroinflammation and Memory Impairment by Modulation of TLR4/NF-kappaB Signaling and CREB/BDNF Expression. Cereb Cortex. 2019 Apr 1;29(4):1430-1438. doi: 10.1093/cercor/bhy039.
• Chen CM, Wu CT, Yang TH, Liu SH, Yang FY. Preventive Effect of Low Intensity Pulsed Ultrasound against Experimental Cerebral Ischemia/Reperfusion Injury via Apoptosis Reduction and Brain-derived Neurotrophic Factor Induction. Sci Rep. 2018 Apr 3;8(1):5568. doi: 10.1038/s41598-018-23929-8.
• Chen SF, Su WS, Wu CH, Lan TH, Yang FY. Transcranial Ultrasound Stimulation Improves Long-Term Functional Outcomes and Protects Against Brain Damage in Traumatic Brain Injury. Mol Neurobiol. 2018 Aug;55(8):7079-7089. doi: 10.1007/s12035-018-0897-z. Epub 2018 Jan 30.
• Su WS, Wu CH, Chen SF, Yang FY. Low-intensity pulsed ultrasound improves behavioral and histological outcomes after experimental traumatic brain injury. Sci Rep. 2017 Nov 14;7(1):15524. doi: 10.1038/s41598-017-15916-2.
• Su WS, Wu CH, Chen SF, Yang FY. Transcranial ultrasound stimulation promotes brain-derived neurotrophic factor and reduces apoptosis in a mouse model of traumatic brain injury. Brain Stimul. 2017 Nov-Dec;10(6):1032-1041. doi: 10.1016/j.brs.2017.09.003. Epub 2017 Sep 7.
• Huang SL, Chang CW, Lee YH, Yang FY. Protective Effect of Low-Intensity Pulsed Ultrasound on Memory Impairment and Brain Damage in a Rat Model of Vascular Dementia. Radiology. 2017 Jan;282(1):113-122. doi: 10.1148/radiol.2016160095. Epub 2016 Jul 11.
• Liu SH, Lai YL, Chen BL, Yang FY. Ultrasound Enhances the Expression of Brain-Derived Neurotrophic Factor in Astrocyte Through Activation of TrkB-Akt and Calcium-CaMK Signaling Pathways. Cereb Cortex. 2017 Jun 1;27(6):3152-3160. doi: 10.1093/cercor/bhw169.
• Su WS, Tsai ML, Huang SL, Liu SH, Yang FY. Controllable permeability of blood-brain barrier and reduced brain injury through low-intensity pulsed ultrasound stimulation. Oncotarget. 2015 Dec 8;6(39):42290-9. doi: 10.18632/oncotarget.5978.
• Lin WT, Chen RC, Lu WW, Liu SH, Yang FY. Protective effects of low-intensity pulsed ultrasound on aluminum-induced cerebral damage in Alzheimer's disease rat model. Sci Rep. 2015 Apr 15;5:9671. doi: 10.1038/srep09671.
• Yang FY, Lu WW, Lin WT, Chang CW, Huang SL. Enhancement of Neurotrophic Factors in Astrocyte for Neuroprotective Effects in Brain Disorders Using Low-intensity Pulsed Ultrasound Stimulation. Brain Stimul. 2015 May-Jun;8(3):465-73. doi: 10.1016/j.brs.2014.11.017. Epub 2014 Dec 4.

Study record dates

Study Major Dates

• Study Start (Actual): August 23, 2019
• Primary Completion (Anticipated): May 31, 2021
• Study Completion (Anticipated): June 30, 2021

Study Registration Dates

• First Submitted: March 28, 2019
• First Submitted That Met QC Criteria: March 29, 2019
• First Posted (Actual): April 1, 2019

Study Record Updates

• Last Update Posted (Actual): April 28, 2020
• Last Update Submitted That Met QC Criteria: April 26, 2020
• Last Verified: April 1, 2020

More Information

Terms related to this study

• Keywords: Alzheimer's Disease; Transcranial Ultrasound Stimulation
• Additional Relevant MeSH Terms: Mental Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurocognitive Disorders; Neurodegenerative Diseases; Dementia; Tauopathies; Alzheimer Disease
• Other Study ID Numbers: TUS01

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No