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Gamma Light and Sound Stimulation to Prevent Dementia in Cognitively Normal People at Risk for Alzheimer's Disease

Primary Purpose

Alzheimer Disease, Family Members

Status
Recruiting
Phase
Not Applicable
Locations
United States
Study Type
Interventional
Intervention
GENUS
Sponsored by
Massachusetts General Hospital
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional prevention trial for Alzheimer Disease focused on measuring Cognitively normal, Alzheimer's disease, Gamma, Amyloid

Eligibility Criteria

55 Years - 90 Years (Adult, Older Adult)All SexesAccepts Healthy Volunteers

Inclusion Criteria: Between 55 - 90 years of age, inclusive. Immediate family history of Alzheimer's disease. Mini-Mental State Exam (MMSE) score of 27 or greater at baseline or expected score range for cognitively normal adjusted for education level. Clinical Dementia Rating Global Score of 0 at baseline. Delayed Recall score on the Logical Memory IIa subtest of 8 to 15 at baseline or expected score range for cognitively normal adjusted for education level. Low serum amyloid levels at baseline. Elevated fibrillar amyloid using 11C PiB PET at baseline between 20 - 70 CL. Willing and able to undergo MRI brain and PET brain scans. Adequate visual and auditory acuity to allow for neuropsychological testing. Able to comply with neuropsychological testing and other study procedures in opinion of site PI. Willing and able to complete baseline assessments, and willing to participate in 13-month study protocol. Willing to provide blood samples at specified timepoints. Willing to consider contributing CSF samples at specified timepoints, if asked. Exclusion Criteria: MRI contraindications, such as presence of pacemakers, aneurysm clips, artificial heart valves, ear implants, metal fragments, or foreign objects in the eyes, skin, or body. High myopia < -7 diopters, or untreated cataracts that affect vision. Any significant systemic illness or unstable medical condition which could lead to difficulty complying with the study protocol. For subjects agreeing to undergo lumbar punctures, history of bleeding disorders or laboratory results indicating low platelet levels are exclusionary for the procedure. Concomitant medications: Treatment with NMDA antagonists. For subjects undergoing lumbar puncture, current use of warfarin or similar anti-coagulants is exclusionary for the procedure. Clinical conditions: History of seizure or medical diagnosis of epilepsy. Female subjects who are pregnant or currently breastfeeding. History of severe allergic or anaphylactic reactions. Longstanding premorbid history (i.e., longer than 10 years) of alcohol or substance abuse with continuous abuse up to and including the time that the symptoms leading to clinical presentation developed. Neurodegenerative disorder associated with cognitive impairment. Renal disease. MR imaging findings such as stroke, tumor, leukoencephalopathy that could preclude meaningful analyses of clinical and imaging data in the opinion of the site PI, such as: Severe leukoencephalopathy seen on MRI. Relevant structural abnormality (i.e., normal pressure or obstructive hydrocephalus, hypoxic ischemic lesions, hemorrhages, tumors, malformations). Cerebral amyloid angiopathy, evidenced by T2* or other susceptibility weighted-MRI. Laboratory findings, if known (study does not perform testing) suggestive of systemic illness such as renal disease. Site investigator's discretion, if s/he feels the subject cannot complete sufficient key study procedures. Exceptions to these guidelines may be considered on a case-by-case basis at the discretion of the Project Director.

Sites / Locations

  • Massachusetts General HospitalRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Sham Comparator

Arm Label

Active GENUS light and sound

Sham GENUS light and sound

Arm Description

The device is a light and sound device that delivers light stimulation using light-emitting diodes (LED) and sound stimulation through a speaker, with a centrally-mounted tablet that plays videos for entertainment. The device will be positioned on an easel such that the tablet is eye level with the participant while they are sitting 5 feet away. The active device delivers light and sound at 40Hz rate.

The device is the same as the active device but it delivers light and sound at different frequencies.

Outcomes

Primary Outcome Measures

Changes in brain amyloid deposition over the study period, as measured by PiB PET.
The investigators will evaluate changes from baseline in amyloid deposition by using Pittsburgh compound B (PiB) PET, which is a standard for AD trial biomarkers, to assess progression towards AD with active or sham treatment.

Secondary Outcome Measures

Changes in brain tau deposition
The investigators will evaluate changes from baseline in tau deposition by using MK-6240 PET
Changes in brain structure using structural MRI
The investigators will evaluate changes in brain structure using structural MRI. Preliminary data show prevention of brain atrophy after 3 months of GENUS as measured by ventricular dilation and hippocampal volume. Using structural MRI, the investigators will evaluate brain volume, cortical thickness and ventricular volume.
Changes in brain electrical activity
The investigators will evaluate brain electrical activity using longitudinal EEG (ie, gamma band power)
Changes in brain connectivity by functional MRI
The investigators will evaluate connectivity using resting state functional MRI to assess changes in brain networks (ie, default mode network).
Changes to rest-activity parameters using actigraphy.
Actigraphy will be used to evaluate rest-activity parameters (ie, interdaily stability
Changes in blood biomarkers of AD
Changes in Alzheimer's blood-based biomarkers (e.g. plasma Aβ42/Aβ40 ratio, Aβ42, Aβ40, p-tau, and neurofilament light) assessed by longitudinal blood sample collection
Compliance of usage as measured by timestamp tracking and eye-tracking technology
The device contains both a time-counter to track 'on time' and a camera that records images for eye-tracking, to quantitatively determine compliance with looking directly at the device. This method also quantifies whether the subjects are awake for the duration of treatment. Previous work with healthy older adults and a small cohort of mild AD patients have had 90% compliance.
Change from baseline in CSF levels of amyloid and tau.
Lumbar puncture and CSF collection will be optional for participants, but will be informative as to the investigator's hypothesized mechanisms of clearance.

Full Information

First Posted
November 29, 2022
Last Updated
September 12, 2023
Sponsor
Massachusetts General Hospital
Collaborators
Massachusetts Institute of Technology
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1. Study Identification

Unique Protocol Identification Number
NCT05776641
Brief Title
Gamma Light and Sound Stimulation to Prevent Dementia in Cognitively Normal People at Risk for Alzheimer's Disease
Official Title
Prevention of Alzheimer's Disease Using Gamma Entrainment
Study Type
Interventional

2. Study Status

Record Verification Date
September 2023
Overall Recruitment Status
Recruiting
Study Start Date
October 1, 2023 (Anticipated)
Primary Completion Date
May 2025 (Anticipated)
Study Completion Date
May 2026 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Massachusetts General Hospital
Collaborators
Massachusetts Institute of Technology

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
Yes
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
Alzheimer's disease (AD) is characterized by significant memory loss, toxic protein deposits (amyloid and tau) in the brain, and changes in the gamma frequency band on EEG. Gamma waves are important for memory, and in patients with AD, there are fewer gamma waves in the brain. The Tsai lab found that boosting gamma waves in AD mouse models using light and sound stimulation at 40Hz not only reduced amyloid and tau in the brain, but also improved memory. A light and sound device was developed for humans that stimulates the brain at 40Hz that can be used safely at home. The goal of this study is to see if using this device can prevent dementia in people who are at risk for developing Alzheimer's disease.
Detailed Description
The investigators are recruiting participants aged 55+ with normal memory who have or had a close family member with Alzheimer's disease. 200 participants will undergo a blood test and a subset will undergo an amyloid PET scan and only 50 participants who have cerebral amyloid deposits will continue in the study. Neither the participant nor the investigators will know whether the participant is receiving sham or active stimulation. Participants will use the device for 12 months at home, for 60 minutes each day when they are awake. Participants will come to the Massachusetts General Hospital in Boston for 4-6 visits: before starting the stimulation, at 6 months, and after 12 months of usage. The participants will undergo PET scans, MRI, EEG, blood tests and memory tests and questionnaires at each visit to monitor progress. In addition, people may elect to allow for us to study their cerebral spinal fluid. Participants will also wear a "fitbit" like watch to monitor sleep and activity throughout the study. The goal of this study is to evaluate whether stimulation with our device at 40Hz will reduce AD pathology in the brain.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Alzheimer Disease, Family Members
Keywords
Cognitively normal, Alzheimer's disease, Gamma, Amyloid

7. Study Design

Primary Purpose
Prevention
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
200 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Active GENUS light and sound
Arm Type
Active Comparator
Arm Description
The device is a light and sound device that delivers light stimulation using light-emitting diodes (LED) and sound stimulation through a speaker, with a centrally-mounted tablet that plays videos for entertainment. The device will be positioned on an easel such that the tablet is eye level with the participant while they are sitting 5 feet away. The active device delivers light and sound at 40Hz rate.
Arm Title
Sham GENUS light and sound
Arm Type
Sham Comparator
Arm Description
The device is the same as the active device but it delivers light and sound at different frequencies.
Intervention Type
Device
Intervention Name(s)
GENUS
Intervention Description
Participants will use the GENUS light and sound device at home for 60 minutes daily for 12 months
Primary Outcome Measure Information:
Title
Changes in brain amyloid deposition over the study period, as measured by PiB PET.
Description
The investigators will evaluate changes from baseline in amyloid deposition by using Pittsburgh compound B (PiB) PET, which is a standard for AD trial biomarkers, to assess progression towards AD with active or sham treatment.
Time Frame
Baseline to 12 months
Secondary Outcome Measure Information:
Title
Changes in brain tau deposition
Description
The investigators will evaluate changes from baseline in tau deposition by using MK-6240 PET
Time Frame
Baseline to 12 months
Title
Changes in brain structure using structural MRI
Description
The investigators will evaluate changes in brain structure using structural MRI. Preliminary data show prevention of brain atrophy after 3 months of GENUS as measured by ventricular dilation and hippocampal volume. Using structural MRI, the investigators will evaluate brain volume, cortical thickness and ventricular volume.
Time Frame
Baseline to 12 months
Title
Changes in brain electrical activity
Description
The investigators will evaluate brain electrical activity using longitudinal EEG (ie, gamma band power)
Time Frame
Baseline to 12 months
Title
Changes in brain connectivity by functional MRI
Description
The investigators will evaluate connectivity using resting state functional MRI to assess changes in brain networks (ie, default mode network).
Time Frame
Baseline to 12 months
Title
Changes to rest-activity parameters using actigraphy.
Description
Actigraphy will be used to evaluate rest-activity parameters (ie, interdaily stability
Time Frame
Baseline to 12 months
Title
Changes in blood biomarkers of AD
Description
Changes in Alzheimer's blood-based biomarkers (e.g. plasma Aβ42/Aβ40 ratio, Aβ42, Aβ40, p-tau, and neurofilament light) assessed by longitudinal blood sample collection
Time Frame
Baseline to 12 months
Title
Compliance of usage as measured by timestamp tracking and eye-tracking technology
Description
The device contains both a time-counter to track 'on time' and a camera that records images for eye-tracking, to quantitatively determine compliance with looking directly at the device. This method also quantifies whether the subjects are awake for the duration of treatment. Previous work with healthy older adults and a small cohort of mild AD patients have had 90% compliance.
Time Frame
Baseline to 12 months
Title
Change from baseline in CSF levels of amyloid and tau.
Description
Lumbar puncture and CSF collection will be optional for participants, but will be informative as to the investigator's hypothesized mechanisms of clearance.
Time Frame
Baseline to 12 months
Other Pre-specified Outcome Measures:
Title
Changes in CSF flow, as measured by BOLD fMRI
Description
The investigators will evaluate changes from baseline in CSF flow by using BOLD fMRI. CSF flow has been linked to amyloid clearance from the brain, and brain waste clearance mechanisms such as blood vessel dilation and increased glymphatic drainage are activated after 40-Hz light and sound stimulation in our preliminary mouse studies
Time Frame
Baseline to 12 months
Title
Change from baseline in integrity of white matter tracks and myelination as measured by diffusion MR imaging.
Description
It is hypothesized that neuromodulation causes changes in synaptic plasticity. The investigators will evaluate plasticity and structural measures of connectivity using diffusion imaging techniques.
Time Frame
Baseline to 12 months
Title
Changes in performance on memory tasks, particularly those that are reliant on visual or auditory pathways, using a neuropsychological test battery.
Description
The investigators will evaluate changes from baseline in performance on memory tasks using a comprehensive neuropsychological battery designed to evaluate pre-clinical AD populations. Preliminary data showed that 3 months of treatment in mild AD patients led to improved performance on an associative memory task.
Time Frame
Baseline to 12 months
Title
Change from baseline in gamma oscillations as measured by EEG
Description
Magnetoencephalogram studies done in AD patients show decreases in endogenous gamma synchronization. We will measure induced gamma entrainment using the GENUS device with EEG.
Time Frame
Baseline to 12 months
Title
Change from baseline in sleep
Description
The investigators will evaluate sleep quality using the Pittsburgh Sleep Quality Index
Time Frame
Baseline to 12 months
Title
Change from baseline in activity levels
Description
The investigators will evaluate activity levels using actigraphy
Time Frame
Baseline to 12 months
Title
Incidence of adverse events
Description
Adverse Events as a result of GENUS stimulation will be reported.
Time Frame
Baseline to 12 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
55 Years
Maximum Age & Unit of Time
90 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion Criteria: Between 55 - 90 years of age, inclusive. Immediate family history of Alzheimer's disease. Mini-Mental State Exam (MMSE) score of 27 or greater at baseline or expected score range for cognitively normal adjusted for education level. Clinical Dementia Rating Global Score of 0 at baseline. Delayed Recall score on the Logical Memory IIa subtest of 8 to 15 at baseline or expected score range for cognitively normal adjusted for education level. Low serum amyloid levels at baseline. Elevated fibrillar amyloid using 11C PiB PET at baseline between 20 - 70 CL. Willing and able to undergo MRI brain and PET brain scans. Adequate visual and auditory acuity to allow for neuropsychological testing. Able to comply with neuropsychological testing and other study procedures in opinion of site PI. Willing and able to complete baseline assessments, and willing to participate in 13-month study protocol. Willing to provide blood samples at specified timepoints. Willing to consider contributing CSF samples at specified timepoints, if asked. Exclusion Criteria: MRI contraindications, such as presence of pacemakers, aneurysm clips, artificial heart valves, ear implants, metal fragments, or foreign objects in the eyes, skin, or body. High myopia < -7 diopters, or untreated cataracts that affect vision. Any significant systemic illness or unstable medical condition which could lead to difficulty complying with the study protocol. For subjects agreeing to undergo lumbar punctures, history of bleeding disorders or laboratory results indicating low platelet levels are exclusionary for the procedure. Concomitant medications: Treatment with NMDA antagonists. For subjects undergoing lumbar puncture, current use of warfarin or similar anti-coagulants is exclusionary for the procedure. Clinical conditions: History of seizure or medical diagnosis of epilepsy. Female subjects who are pregnant or currently breastfeeding. History of severe allergic or anaphylactic reactions. Longstanding premorbid history (i.e., longer than 10 years) of alcohol or substance abuse with continuous abuse up to and including the time that the symptoms leading to clinical presentation developed. Neurodegenerative disorder associated with cognitive impairment. Renal disease. MR imaging findings such as stroke, tumor, leukoencephalopathy that could preclude meaningful analyses of clinical and imaging data in the opinion of the site PI, such as: Severe leukoencephalopathy seen on MRI. Relevant structural abnormality (i.e., normal pressure or obstructive hydrocephalus, hypoxic ischemic lesions, hemorrhages, tumors, malformations). Cerebral amyloid angiopathy, evidenced by T2* or other susceptibility weighted-MRI. Laboratory findings, if known (study does not perform testing) suggestive of systemic illness such as renal disease. Site investigator's discretion, if s/he feels the subject cannot complete sufficient key study procedures. Exceptions to these guidelines may be considered on a case-by-case basis at the discretion of the Project Director.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Kenji Aoki, BA
Phone
617-258-7723
Email
kenji292@mit.edu
First Name & Middle Initial & Last Name or Official Title & Degree
Gabrielle de Weck, BS
Phone
617-258-7723
Email
gdeweck@mit.edu
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Diane Chan, MD PhD
Organizational Affiliation
Massachusetts General Hospital
Official's Role
Principal Investigator
Facility Information:
Facility Name
Massachusetts General Hospital
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02114
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Kenji Aoki, BA
Phone
617-258-7723
Email
kenji292@mit.edu
First Name & Middle Initial & Last Name & Degree
Gabrielle de Weck, BS
Phone
617-258-7723
Email
gdeweck@mit.edu
First Name & Middle Initial & Last Name & Degree
Diane Chan, MD PhD

12. IPD Sharing Statement

Plan to Share IPD
No

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Gamma Light and Sound Stimulation to Prevent Dementia in Cognitively Normal People at Risk for Alzheimer's Disease

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