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tACS for Amyloid-β Reduction in Alzheimer's Disease

Primary Purpose

Alzheimer Disease

Status

Completed

Phase

Not Applicable

Locations

United States

Study Type

Interventional

Intervention

Transcranial Alternating Current Stimulation (tACS)

About this trial

This is an interventional treatment trial for Alzheimer Disease focused on measuring Alzheimer, Memory Problems

Eligibility Criteria

45 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Clinical Diagnosis of mild AD defined by: Clinical Dementia Rating (CDR) = 0.5-1, Mini Mental State Examination (MMSE) >/= 20, Demonstration or history of memory impairments
Amyloid positive PET imaging
At least 45 years old
On a stable dose of medications for memory loss including cholinesterase inhibitors (e.g. donepezil, rivastigmine or memantine) as defined as 6 consecutive weeks of treatment at an unchanging dose
Intelligence Quotient (IQ) > 85 as determined by the Wechsler Test of Adult Reading (WTAR) and no history of intellectual disability

Exclusion Criteria:

Current history of poorly controlled migraines including chronic medication for migraine prevention
Current or past history of any neurological disorder other than dementia, such as epilepsy, stroke, progressive neurologic disease (e.g. multiple sclerosis) or intracranial brain lesions; and history of previous neurosurgery or head trauma that resulted in residual neurologic impairment.
Past or current history of major depression, bipolar disorder or psychotic disorders, or any other major psychiatric condition.
Contraindication for undergoing MRI or receiving Transcranial Magnetic Stimulation (TMS) or tACS,
• History of fainting spells of unknown or undetermined etiology that might constitute seizures.
History of seizures, diagnosis of epilepsy, history of abnormal (epileptiform) EEG or immediate (1st degree relative) family history of epilepsy; with the exception of a single seizure of benign etiology (e.g. febrile seizure) in the judgment of the investigator.
Chronic (particularly) uncontrolled medical conditions that may cause a medical emergency in case of a provoked seizure (cardiac malformation, cardiac dysrhythmia, asthma, etc.).
Metal implants (excluding dental fillings) or devices such as pacemaker, medication pump, nerve stimulator, Transcutaneous Electrical Nerve Stimulator (TENS) unit, ventriculo-peritoneal shunt, cochlear implant, unless cleared by the study MD.
Substance abuse or dependence within the past six months.
Medications will be reviewed by the responsible MD and a decision about inclusion will be made based on the following: The patient's past medical history, drug dose, history of recent medication changes or duration of treatment, and combination of Central Nervous System (CNS) active drugs.
All female participants that are pre-menopausal will be required to have a pregnancy test; any participant who is pregnant will not be enrolled in the study.
BMI > 40 kg/m2. We will limit the BMI to <40 kg/m2 because of weight limits of the scanner bed and width limits of the MRI.
Subjects who, in the investigator's opinion, might not be suitable for the study
A hair style or head dress that prevents electrode contact with the scalp or would interfere with the stimulation (for example: thick braids, hair weave, afro, wig)

Sites / Locations

Beth Israel Deaconess Medical Center

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

tACS

Arm Description

Transcranial alternating current stimulation (tACS) tuned at the frequency of 40Hz (gamma frequency) will be applied for 1 hour in 10 sessions on consecutive weekdays. The tACS intervention (10 sessions) will be preceded and followed by amyloid PET imaging as well as a clinical/cognitive evaluation. The assessment of adverse effects will constitute a Primary outcome measure. Changes in amyloid load in the stimulated brain region will be evaluated and constitute a secondary outcome of the study. Clinically relevant changes in cognitive and clinical scores will be also evaluated as secondary outcomes. Stimulation will be also preceded and followed by electroencephalography (EEG) recording aimed at assessing changes in spectral power in the gamma band.

Outcomes

Primary Outcome Measures

Change in Amyloid Burden

Changes in the amyloid load observed via PET imaging will be evaluated by comparing PET data acquired before and after the 10 tACS sessions. The metric used is SUVR, a measure of the amount of proteins in the brain identified at the PET exam. We will calculate the difference between pre and post tACS SUVR (dSUVR) for the entire brain and report the average value (and standard deviation) for the entire group of patients. A negative value express a decrease in the amount of proteins in the brain post tACS intervention. It must be considered that dSUVR values refer to the entire brain, however patients were treated according to personalized tACS montages targeting patient-specific regions mostly affected by the pathology. This might have led to slightly different changes in SUVR in different part of the brain across participants. Also, as per standard procedures, results are presented at group level, i.e. without considering individual differences in longitudinal amyloid load changes.

Secondary Outcome Measures

Change in EEG Gamma-band Spectral Power

EEG power spectral densities (PSD) before and after the tACS intervention were evaluated, specifically absolute and relative power density values (μV2/Hz) were calculated within the gamma band (35-45Hz). Changes in the spectral power are reported in term of percentage of changes in relative spectral power from Pre to Post tACS intervention.

Change in Adas-Cog Score

Change in Adas-Cog score will be reported, to document a potential clinical benefit of tACS. The scale ranges from a total score of 0-70 with higher score indicating greater cognitive impairment.

Full Information

NCT ID

NCT03290326

First Posted

September 15, 2017

Last Updated

August 18, 2022

Sponsor

Massachusetts General Hospital

1. Study Identification

Unique Protocol Identification Number

NCT03290326

Brief Title

tACS for Amyloid-β Reduction in Alzheimer's Disease

Official Title

Feasibility and Safety of a High-Frequency Transcranial Alternating Current Stimulation Intervention for Amyloid-β Reduction in Alzheimer's Disease

Study Type

Interventional

2. Study Status

Record Verification Date

August 2022

Overall Recruitment Status

Completed

Study Start Date

November 27, 2017 (Actual)

Primary Completion Date

May 14, 2019 (Actual)

Study Completion Date

May 14, 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Massachusetts General Hospital

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Yes

Device Product Not Approved or Cleared by U.S. FDA

Yes

Product Manufactured in and Exported from the U.S.

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

Alzheimer's Disease (AD) is characterized by amyloid-β (Aβ) plaque buildup and phosphorylated tau (p-tau) in the brain, as well as widespread neurodegeneration. The evidence suggests that both amyloid and tau play a critical role in AD and interventions that reliably and safely decrease the intracerebral burden of amyloid or tau could potentially be of marked clinical importance. Currently, therapeutic options are very limited and while there are pharmacologic interventions that transiently improve cognitive function, there are no treatments that alter disease progression. The current study seeks to use a novel therapeutic intervention that uses noninvasive brain stimulation to target amyloid in the brain. The investigators anticipate this will decrease the amyloid levels in the brain, as evidence by Positron Emission Tomography (PET) imaging.

Detailed Description

Alzheimer's Disease (AD) is characterized by amyloid-β (Aβ) plaque buildup and phosphorylated tau (p-tau) in the brain, as well as widespread neurodegeneration. There is no current treatments that alter disease progression. Investigators will recruit 20 individuals with AD with evidence of amyloid placques in the brain through Positron Emission Tomography (PET) imaging. Investigators will use a novel approach, transcranial alternating current stimulation (tACS), to target the region of maximum amyloid burden in the brain. All participants will receive tACS. Each individual's participation in the study will consist of approximately 16 visits: 3 days for screening/baseline procedures as described below, 10 tACS study visits, and 3 days for follow-up assessments. Subjects will undergo baseline cognitive assessment, structural and functional MRI characterization, and resting-state EEG measurement. Additionally, patients will undergo a tACS-EEG recording session to assess brain plasticity levels and identify markers of response to stimulation. All subjects will then undergo 10 1-hour sessions of gamma-frequency (40 Hz) tACS, targeted to the region of maximal tracer uptake on the amyloid PET study. Subjects will take a standardized adverse effect questionnaire before and after each session and complete a short cognitive test after each session to demonstrate safety and tolerability. At the end of the 10 sessions, subjects will then repeat the baseline assessments, followed by repeat amyloid PET imaging to assess for changes in amyloid burden. Investigators anticipate that targeting the region of amyloid burden in the brain with tACS will reduce the amyloid burden as evidence by the follow up PET imaging and show improvement on electrophysiological measures of brain function and on cognitive testing. If our prediction is correct, this will will provide a critical first step in the development of a novel intervention to prevent and treat AD.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Alzheimer Disease

Keywords

Alzheimer, Memory Problems

7. Study Design

Primary Purpose

Treatment

Study Phase

Not Applicable

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

17 (Actual)

8. Arms, Groups, and Interventions

Arm Title

tACS

Arm Type

Experimental

Arm Description

Intervention Type

Device

Intervention Name(s)

Transcranial Alternating Current Stimulation (tACS)

Intervention Description

tACS will be applied at a frequency of 40Hz and targeting the area of maximal tracer uptake on amyloid PET imaging using an individualized multielectrode design to maximize the induced electrical current to the target region.

Primary Outcome Measure Information:

Title

Change in Amyloid Burden

Description

Time Frame

Up to six weeks

Secondary Outcome Measure Information:

Title

Change in EEG Gamma-band Spectral Power

Description

Time Frame

Up to six weeks

Title

Change in Adas-Cog Score

Description

Change in Adas-Cog score will be reported, to document a potential clinical benefit of tACS. The scale ranges from a total score of 0-70 with higher score indicating greater cognitive impairment.

Time Frame

Up to six weeks

10. Eligibility

Sex

All

Minimum Age & Unit of Time

45 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Clinical Diagnosis of mild AD defined by: Clinical Dementia Rating (CDR) = 0.5-1, Mini Mental State Examination (MMSE) >/= 20, Demonstration or history of memory impairments Amyloid positive PET imaging At least 45 years old On a stable dose of medications for memory loss including cholinesterase inhibitors (e.g. donepezil, rivastigmine or memantine) as defined as 6 consecutive weeks of treatment at an unchanging dose Intelligence Quotient (IQ) > 85 as determined by the Wechsler Test of Adult Reading (WTAR) and no history of intellectual disability Exclusion Criteria: Current history of poorly controlled migraines including chronic medication for migraine prevention Current or past history of any neurological disorder other than dementia, such as epilepsy, stroke, progressive neurologic disease (e.g. multiple sclerosis) or intracranial brain lesions; and history of previous neurosurgery or head trauma that resulted in residual neurologic impairment. Past or current history of major depression, bipolar disorder or psychotic disorders, or any other major psychiatric condition. Contraindication for undergoing MRI or receiving Transcranial Magnetic Stimulation (TMS) or tACS, • History of fainting spells of unknown or undetermined etiology that might constitute seizures. History of seizures, diagnosis of epilepsy, history of abnormal (epileptiform) EEG or immediate (1st degree relative) family history of epilepsy; with the exception of a single seizure of benign etiology (e.g. febrile seizure) in the judgment of the investigator. Chronic (particularly) uncontrolled medical conditions that may cause a medical emergency in case of a provoked seizure (cardiac malformation, cardiac dysrhythmia, asthma, etc.). Metal implants (excluding dental fillings) or devices such as pacemaker, medication pump, nerve stimulator, Transcutaneous Electrical Nerve Stimulator (TENS) unit, ventriculo-peritoneal shunt, cochlear implant, unless cleared by the study MD. Substance abuse or dependence within the past six months. Medications will be reviewed by the responsible MD and a decision about inclusion will be made based on the following: The patient's past medical history, drug dose, history of recent medication changes or duration of treatment, and combination of Central Nervous System (CNS) active drugs. All female participants that are pre-menopausal will be required to have a pregnancy test; any participant who is pregnant will not be enrolled in the study. BMI > 40 kg/m2. We will limit the BMI to <40 kg/m2 because of weight limits of the scanner bed and width limits of the MRI. Subjects who, in the investigator's opinion, might not be suitable for the study A hair style or head dress that prevents electrode contact with the scalp or would interfere with the stimulation (for example: thick braids, hair weave, afro, wig)

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Emiliano Santarnecchi

Organizational Affiliation

Massachusetts General Hospital

Official's Role

Principal Investigator

Facility Information:

Facility Name

Beth Israel Deaconess Medical Center

City

Boston

State/Province

Massachusetts

ZIP/Postal Code

02215

Country

United States

12. IPD Sharing Statement

Citations:

PubMed Identifier

34930421

Citation

Sprugnoli G, Munsch F, Cappon D, Paciorek R, Macone J, Connor A, El Fakhri G, Salvador R, Ruffini G, Donohoe K, Shafi MM, Press D, Alsop DC, Pascual Leone A, Santarnecchi E. Impact of multisession 40Hz tACS on hippocampal perfusion in patients with Alzheimer's disease. Alzheimers Res Ther. 2021 Dec 20;13(1):203. doi: 10.1186/s13195-021-00922-4.

Results Reference

derived

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tACS for Amyloid-β Reduction in Alzheimer's Disease

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