An interventional study of Transcranial Alternating Current Stimulation (tACS) in Alzheimer Disease, sponsored by Massachusetts General Hospital. Completed at 1 site in United States. Open to participants aged 45 Years and older. Per ClinicalTrials.gov, last updated 2022-08-22.
Sponsored by Massachusetts General Hospital · Not applicable, Interventional, and Treatment
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.
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.
Exclusion Criteria:
Contraindication for undergoing MRI or receiving Transcranial Magnetic Stimulation (TMS) or tACS,
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.
Device: Transcranial Alternating Current Stimulation (tACS)
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.
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.
Time frame: Up to six weeks
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.
Time frame: Up to six weeks
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.
Time frame: Up to six weeks
Of 17 enrolled participants, 10 met inclusion criteria and underwent transcranial alternating current stimulation (tACS)
| Milestone | tACS |
|---|---|
| Started | 10 |
| Completed | 10 |
| Not completed | 0 |
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.
| dSUVR | tACS |
|---|---|
| Change in Amyloid Burden | -1.55 ± 0.9 |
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.
| % difference in spectral power (μV2/Hz) | tACS 40Hz |
|---|---|
| Change in EEG Gamma-band Spectral Power | 23.5 ± 13.4 |
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.
| Scores on a scale | tACS |
|---|---|
| Change in Adas-Cog Score | -0.97 ± 3.88 |
Collected over 5 months. Non-serious events are listed at a 0% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| tACS | 0/10 (0%) | 0/10 (0%) | 8/10 (80%) |
| Event | tACS |
|---|---|
| Sensations under electrodesGeneral disorders | 8/10 |
| Visual ChangesGeneral disorders | 6/10 |
| Skin IrritationGeneral disorders | 5/10 |
| NervousnessGeneral disorders | 3/10 |
| HeadacheGeneral disorders | 2/10 |
| Scalp PainGeneral disorders | 2/10 |
| Neck PainGeneral disorders | 2/10 |
| Difficulty concentratingGeneral disorders | 2/10 |
| Hand tinglingGeneral disorders | 1/10 |
| Eye painGeneral disorders | 1/10 |
| Age, Customized(Participants) | tACS |
|---|---|
| Age — 55 | 1 |
| Age — 57 | 1 |
| Age — 63 | 1 |
| Age — 75 | 1 |
| Age — 76 | 2 |
| Age — 78 | 2 |
| Age — 79 | 1 |
| Age — 83 | 1 |
| Sex: Female, Male(Participants) | tACS |
|---|---|
| Female | 4 |
| Male | 6 |
| Race (NIH/OMB)(Participants) | tACS |
|---|---|
| American Indian or Alaska Native | 0 |
| Asian | 0 |
| Native Hawaiian or Other Pacific Islander | 0 |
| Black or African American | 0 |
| White | 10 |
| More than one race | 0 |
| Unknown or Not Reported | 0 |
| Region of Enrollment(participants) | tACS |
|---|---|
| United States | 10 |
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Massachusetts General Hospital