At Home Gamma tACS in Alzheimer's Disease (tACS@Home)

Study Overview
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Brief Summary
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Brain oscillations are ubiquitous in the human brain and have been implicated in cognitive and behavioral states defined in precisely tuned neural networks. In neurodegenerative disorders, neurodegeneration is accompanied by changes in oscillatory activity leading to the emerging concept of neurological and psychiatric disorders as oscillopathies. Alzheimer's disease, which accounts for the vast majority of age-related dementias, is characterised by a prominent disruption of oscillations in the gamma frequency band. The restoration of gamma oscillations by neural entrainment in animal models of Alzheimer's disease have shown a remarkable decrease in the pathological burden of amyloid and tau via increased microglial activity, resulting in a significant increase of cognitive performances. Transcranial alternating current brain stimulation (tACS), is a neurophysiological method of non-invasive modulation of the excitability of the central nervous system that is having an increasingly numerous spectrum of potential therapeutic applications. Recent studies have demonstrated the effectiveness of this method in modulating the natural frequencies of cerebral oscillation, underlying multiple cognitive processes such as verbal memory, perception and working memory. On the basis of these premises, the treatment with gamma tACS is proposed in patients affected by Alzheimer's disease. In this randomized, double-blind, sham-controlled study, followed by an open-label phase, the investigators will evaluate whether a 9- or 18-weeks treatment with gamma tACS over the precuneus, delivered at home, can improve symptoms in patients with mild Alzheimer's disease.

Detailed Description
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Brain oscillations are ubiquitous in the human brain and have been implicated in cognitive and behavioral states defined in precisely tuned neural networks. In neurodegenerative disorders, neurodegeneration is accompanied by changes in oscillatory activity leading to the emerging concept of neurological and psychiatric disorders as oscillopathies. Alzheimer's disease, which accounts for the vast majority of age-related dementias, is characterised by a prominent disruption of oscillations in the gamma frequency band. The restoration of gamma oscillations by neural entrainment in animal models of Alzheimer's disease have shown a remarkable decrease in the pathological burden of amyloid and tau via increased microglial activity, resulting in a significant increase of cognitive performances. Transcranial alternating current brain stimulation (tACS), is a neurophysiological method of non-invasive modulation of the excitability of the central nervous system that is having an increasingly numerous spectrum of potential therapeutic applications. Recent studies have demonstrated the effectiveness of this method in modulating the natural frequencies of cerebral oscillation, underlying multiple cognitive processes such as verbal memory, perception and working memory. On the basis of these premises, the treatment with gamma tACS is proposed in patients affected by Alzheimer's disease. In this randomized, double-blind, sham-controlled study, followed by an open-label phase, the investigators will evaluate whether a 9- or 18-weeks treatment with gamma tACS over the precuneus, delivered at home, can improve symptoms in patients with mild Alzheimer's disease. Subjects will be randomized in two groups in the first part of the trial. One group will receive a two-months treatment with gamma tACS (40 Hz) over the precuneus while the other group will receive placebo (sham) stimulation. After two-months, both group will undergo real stimulation (open-label phase) with gamma tACS (40 Hz) over the precuneus for two-months. Modulators of response will be considered.

Official Title
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Markers of Clinical and Biological Response to Home Delivered Transcranial Alternating Current Stimulation (tACS) in Patients With Alzheimer's Disease

Conditions
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Alzheimer Disease

Intervention / Treatment
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* Device: 40 Hz transcranial alternating current stimulation
* Device: Sham stimulation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria for the Patient: Mild Alzheimer's disease (CDR 0.5 - 1) Exclusion Criteria for the Patient: Cerebrovascular disorders Previous stroke Hydrocephalus Intra-cranial mass documented by MRI History of traumatic brain injury or other neurological diseases Serious medical illness other than AD History of seizures Pregnancy Metal implants in the head (except dental fillings) Electronic implants (i.e. pace-maker, implanted medical pump) Age <18 years Inclusion Criteria for the Caregiver: Age > 18 years Compliance in participation in training on the use of the therapeutic device Mini-Mental State Examination >26/30

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Real tACS - Real tACS<br>42 sessions of 40 Hz transcranial alternating current stimulation (5 days/week for 9 weeks) followed by an open-label 42 sessions of 40 Hz transcranial alternating current stimulation (5 days/week for 9 weeks). | Device: 40 Hz transcranial alternating current stimulation<br>* 42 sessions of 40 Hz transcranial alternating current stimulation (5 days/week for 9 weeks)<br>|
| Sham Comparator: Sham tACS - Real tACS<br>42 sessions of sham stimulation (5 days/week for 9 weeks) followed by an open-label 42 sessions of 40 Hz transcranial alternating current stimulation (5 days/week for 9 weeks). | Device: 40 Hz transcranial alternating current stimulation<br>* 42 sessions of 40 Hz transcranial alternating current stimulation (5 days/week for 9 weeks)<br>Device: Sham stimulation<br>* 42 sessions of sham stimulation (5 days/week for 9 weeks)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety of transcranial alternating current stimulation delivered at home | Incidence of Treatment-Emergent Adverse Events as assessed by the incidence of adverse events graded from 1 (mild) to 5 (fatal). | Through study completion, at week 26 | 
| Tolerability of transcranial alternating current stimulation delivered at home | Tolerability will be evaluated with percentage of compliance (number of delivered stimulations divided by number of programmed stimulations times one-hundred) The primary outcome will be reached if compliance will be >90%. | Through study completion, at week 26 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in Clinical Dementia Rating scale (CDR) sum of boxes | CDR-SB scores range from 0 to 18, with higher scores indicating worse cog- nition and daily function. | Change from baseline to week 9 - 18 - 26 | 
| Changes in Alzheimer's Disease Assessment Scale Cognitive Subscale (ADAS-Cog)13 | ADAS-Cog13 scores range from 0 to 85, with higher scores indicating a greater deficit. | Change from baseline to week 9 - 18 - 26 | 
| Changes in Rey Auditory Verbal Learning Test scores | Participants are given a list of 15 unrelated words repeated over five different trials and are asked to repeat. Another list of 15 unrelated words are given and the patient must again repeat the original list of 15 words and then again after 30 minutes. The score ranges from 0 (worse performance) to 15 (best performance). | Change from baseline to week 9 - 18 - 26 | 
| Changes in Face-Name Associative Memory Test (FNAT) scores | The Face-Name Associative Memory Test is a cross-modal associative memory test, it includes 20 face-name pairs. The administration procedure starts with the presentation of 20 faces with each name and participants should read the name underneath the faces and try to learn each face-name pair. After 5 minutes, the faces are shown one by one and participants are asked to recall the associated names from 4 different names. The correct number of pairs recalled is recorded. The score ranges from 0 (worse performance) to 20 (best performance). | Change from baseline to week 9 - 18 - 26 | 
| Changes in Face-Name Neuropsychiatric Inventory (NPI-Q) | The NPI-Q is designed to be an informant-based interview that assesses neuropsychiatric symptoms of the participant over the previous month. The score ranges from 0 (no symptoms) to 180 (severe symptoms). | Change from baseline to week 9 - 18 - 26 | 
| Changes in Zarit Burden Interview (ZBI) | The Zarit Burden Inventory is an interview used to evaluate the consequences that the care burden of a family member with chronic or degenerative pathologies has on the caregiver. It is a tool that can be used both in self-report form and in the form of a structured interview and is made up of 22 items. It requires the caregiver to respond using a Likert scale from 0 (never) to 4 (almost always) based on the degree of agreement with the individual items. The items investigate how the patient's disability impacts on the caregiver's quality of life, psychological distress, guilt, financial difficulties, shame, and social and family difficulties. The score ranges from 0 (no burden) to 88 (severe burden). | Change from baseline to week 9 - 18 - 26 | 
| Changes in Caregiver Burden Inventory (CBI) | The Caregiver Burden Inventory (CBI) includes 24 items and 5 dimensions: Time-dependence, developmental, physical, emotional, and social burden. There are 5 items for each dimension, except for the physical dimension, which has four items. Each item signifies a score between zero (not descriptive) and four (highly descriptive), with a higher score indicating greater care burden. Therefore the total score for time-dependence, developmental, emotional, and social burden range from 0 to 20 except for physical burden where scores range from 0 to 16. The total score ranges from 0 (no burden) to 96 (severe burden). | Change from baseline to week 9 - 18 - 26 | 
| Change in SAI measurements | By using transcranial magnetic stimulation (TMS), the investigators will evaluate the effects of gamma tACS on short latency afferent inhibition (SAI), which is a marker of cholinergic transmission. SAI is expressed as % of the unconditioned motor evoked potential. | Change from baseline to week 9 - 18 - 26 | 
| Change in EEG gamma power | By using electroencephalography (EEG), the investigators will evaluate the change in gamma power. | Change from baseline to week 9 - 18 - 26 | 
| Change in plasma NfL levels | Changes in plasma neurofilament light (NfL) levels (pg/mL) will be evaluated. | Change from baseline to week 9 - 18 - 26 | 
| Change in plasma GFAP levels | Changes in plasma glial fibrillary acidic protein (GFAP) levels (pg/mL) will be evaluated. | Change from baseline to week 9 - 18 - 26 | 
| Change in plasma amyloid beta1-40 levels | Change in plasma amyloid beta1-40 levels (pg/mL) will be evaluated. | Change from baseline to week 9 - 18 - 26 | 
| Change in plasma amyloid beta1-42 levels | Change in plasma amyloid beta1-42 levels (pg/mL) will be evaluated. | Change from baseline to week 9 - 18 - 26 | 
| Change in brain amyloid plaque burden | Change in standardized uptake value ratio (SUVR) of amyloid placque burden evaluated with amyloid PET. | Change from baseline to week 9 | 
| Change in resting state MRI connectivity | Change in resting state magnetic resonance imaging connectivity (default mode network) both static and dynamic. | Change from baseline to week 9 - 18 - 26 |