Alzheimer Disease
Conditions
Keywords
Alzheimer Disease
Brief summary
This study aims to implement an intervention based on multiple, individualized multifocal tACS stimulation sessions based on individual PET and MRI information in patients with amyloid-positive PET with the hope that this leads to microglia activation and decrease in cerebral amyloid and tau depositions in human patients with AD.
Detailed description
This study will leverage all this accumulated knowledge by implementing an intervention based on multiple, individualized multifocal tACS stimulation sessions based on individual PET and MRI information in patients with amyloid-positive PET with the hope that this leads to microglia activation and decrease in cerebral amyloid and tau depositions in human patients with AD.This would have immense translational impact, as gamma tACS is an intervention that is portable, does not require expensive hardware, can be widely applied to large numbers of patients with AD, as well as, given its favorable side effect profile, even to patients at earlier stages of the disease who have cerebral amyloid/tau without clinical symptoms. The investigators aim to enroll 10 individuals with AD with evidence of increased cerebral amyloid burden on amyloid PET imaging. This would allow for a final sample size of 5-6 fully evaluable subjects. Each subject's participation in this study will consist of approximately 31-35 visits: 1 day for consent and screening procedures, 5-7 days of baseline procedures (this includes the PET scans), 20 tACS study visits, and 5-7 days of follow-up assessments. Subjects will undergo baseline cognitive assessment, structural and functional MRI characterization, PET imaging to assess amyloid burden, tau deposition and level of microglia activation, and resting-state EEG measurement. Additionally, subjects will undergo a TMS-EEG and a tACS-EEG recording session to assess brain plasticity levels and identify markers of response to stimulation. All subjects will subsequently undergo 20 sessions of gamma-frequency (40 Hz) tACS. At the end of the 20 sessions, subjects will then repeat the baseline assessments over 5-7 visits, including repeat PET imaging to assess for changes in amyloid burden, tau deposition, and microglia activation.
Interventions
DEVICETranscranial 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.
Sponsors
Defense Advanced Research Projects Agency
Massachusetts General Hospital
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
45 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Clinical Diagnosis of mild to moderate AD\* * Mini Mental State Examination (MMSE) \> 18 * Mild AD ≥ 21 * Moderate AD 18-20 * Demonstration or history of memory impairments. \* Confirmation of diagnosis will be made by the study MD based on a holistic consideration of the participant's cognitive evaluation and history. * 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 * Minimum of completed 8th grade education * IQ\> 85 as determined by the 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 TMS or tACS, * \>50 mSv of radiation exposure for research within the past year (PET imaging exclusion) * Presence of the Thr/Thr polymorphism in the TSPO gene (rs6971) due to low affinity binding for the PBR 28 (microlgia) PET scan * 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, 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 CNS active drugs. * All female participants that are pre-menopausal will be required to have a pregnancy test; any participant who is pregnant or breastfeeding will not be enrolled in the study. * 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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| PET Amyloid Burden | baseline and up to 12 weeks | Changes in the amyloid load observed via PET imaging will be evaluated by comparing PET data acquired before and after the 20 tACS sessions. The metric used is standardized uptake value ratio (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 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. |
| PET Tau Deposition | up to 12 weeks | Changes in the tau deposition observed via PET imaging will be evaluated by comparing PET data acquired before and after the 20 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| PET Microglia Activation | up to 12 weeks | Changes in the microglia activation observed via PET imaging will be evaluated by comparing PET data acquired before and after the 20 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. |
| Changes in Brain Perfusion as Measured by Arterial Spin Labeling | 6 weeks (pre-post tACS intervention) | Patients underwent a comprehensive MRI exam before and after the tACS intervention, including measures of brain perfusion via Arterial Spin Labeling (ASL) sequences. The outcome measure represent the average change in perfusion (i.e. blood flow) recorded in regions targeted by tACS. Since Alzheimer's Disease is also characterized by a decrease of brain metabolism, an increased of blood flow after treatment would constitute a very promising sign of tACS efficacy in reducing Alzheimer's pathology in the brain. We will report the change in blood flow (mean, standard deviation) after tACS treatment. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Alzheimer's Disease Assessment Scale -Cog Score | up to 12 weeks | Change in Adas-Cog score will be reported, to document a potential clinical benefit of tACS. The scale ranges from 0-70 with higher score indicating greater cognitive impairment. |
Countries
United States
Participant flow
Recruitment details
5 participants were enrolled in the study. 4 out of 5 participants completed the study. 1 study subject did not complete the follow-up amyloid and tau PET scans.
Participants by arm
| Arm | Count |
|---|---|
| tACS Transcranial alternating current stimulation (tACS) tuned at the frequency of 40Hz (gamma frequency) will be applied for 1 hour in 20 sessions on consecutive weekdays. The tACS intervention (20 sessions) will be preceded and followed by amyloid, microglia and tau PET imaging as well as a clinical/cognitive evaluation. The assessment of the effect of stimulation on microglia activation, amyloid deposition and tau deposition will constitute a primary outcome measure. Assessment of adverse effects will be also evaluated as a secondary outcome. The effect of brain stimulation on brain connectivity will be assessed by EEG and MRI and cognitive function.
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. | 5 |
| Total | 5 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | tACS |
|---|---|
| Age, Customized 56 | 1 Participants |
| Age, Customized 64 | 1 Participants |
| Age, Customized 73 | 1 Participants |
| Age, Customized 84 | 2 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 5 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 5 Participants |
| Region of Enrollment United States | 5 participants |
| Sex: Female, Male Female | 1 Participants |
| Sex: Female, Male Male | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 5 |
| other Total, other adverse events | 5 / 5 |
| serious Total, serious adverse events | 1 / 5 |
Outcome results
Primary
PET Amyloid Burden
Changes in the amyloid load observed via PET imaging will be evaluated by comparing PET data acquired before and after the 20 tACS sessions. The metric used is standardized uptake value ratio (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 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.
Time frame: baseline and up to 12 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| tACS | PET Amyloid Burden | -1.11 SUVR | Standard Deviation 0.76 |
Primary
PET Tau Deposition
Changes in the tau deposition observed via PET imaging will be evaluated by comparing PET data acquired before and after the 20 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.
Time frame: up to 12 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| tACS | PET Tau Deposition | -2.85 SUVR | Standard Deviation 1.2 |
Secondary
Changes in Brain Perfusion as Measured by Arterial Spin Labeling
Patients underwent a comprehensive MRI exam before and after the tACS intervention, including measures of brain perfusion via Arterial Spin Labeling (ASL) sequences. The outcome measure represent the average change in perfusion (i.e. blood flow) recorded in regions targeted by tACS. Since Alzheimer's Disease is also characterized by a decrease of brain metabolism, an increased of blood flow after treatment would constitute a very promising sign of tACS efficacy in reducing Alzheimer's pathology in the brain. We will report the change in blood flow (mean, standard deviation) after tACS treatment.
Time frame: 6 weeks (pre-post tACS intervention)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| tACS | Changes in Brain Perfusion as Measured by Arterial Spin Labeling | 1.2 mg/min/100gr | Standard Deviation 0.6 |
Secondary
PET Microglia Activation
Changes in the microglia activation observed via PET imaging will be evaluated by comparing PET data acquired before and after the 20 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.
Time frame: up to 12 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| tACS | PET Microglia Activation | -0.56 SUVR | Standard Deviation 1.08 |
Other Pre-specified
Alzheimer's Disease Assessment Scale -Cog Score
Change in Adas-Cog score will be reported, to document a potential clinical benefit of tACS. The scale ranges from 0-70 with higher score indicating greater cognitive impairment.
Time frame: up to 12 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| tACS | Alzheimer's Disease Assessment Scale -Cog Score | 1.5 Scores on a scale | Standard Deviation 2.9 |