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

Primary Purpose

Alzheimer Disease

Status
Recruiting
Phase
Not Applicable
Locations
Italy
Study Type
Interventional
Intervention
40 Hz transcranial alternating current stimulation
Sham stimulation
Sponsored by
Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Alzheimer Disease

Eligibility Criteria

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

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

Sites / Locations

  • ASST Spedali Civili di BresciaRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Sham Comparator

Arm Label

Real tACS - Real tACS

Sham tACS - Real tACS

Arm Description

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).

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).

Outcomes

Primary Outcome Measures

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).
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%.

Secondary Outcome Measures

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.
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.
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).
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).
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).
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).
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 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 in EEG gamma power
By using electroencephalography (EEG), the investigators will evaluate the change in gamma power.
Change in plasma NfL levels
Changes in plasma neurofilament light (NfL) levels (pg/mL) will be evaluated.
Change in plasma GFAP levels
Changes in plasma glial fibrillary acidic protein (GFAP) levels (pg/mL) will be evaluated.
Change in plasma amyloid beta1-40 levels
Change in plasma amyloid beta1-40 levels (pg/mL) will be evaluated.
Change in plasma amyloid beta1-42 levels
Change in plasma amyloid beta1-42 levels (pg/mL) will be evaluated.
Change in brain amyloid plaque burden
Change in standardized uptake value ratio (SUVR) of amyloid placque burden evaluated with amyloid PET.
Change in resting state MRI connectivity
Change in resting state magnetic resonance imaging connectivity (default mode network) both static and dynamic.

Full Information

First Posted
November 24, 2022
Last Updated
December 7, 2022
Sponsor
Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia
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1. Study Identification

Unique Protocol Identification Number
NCT05643326
Brief Title
At Home Gamma tACS in Alzheimer's Disease (tACS@Home)
Acronym
tACS@Home
Official Title
Markers of Clinical and Biological Response to Home Delivered Transcranial Alternating Current Stimulation (tACS) in Patients With Alzheimer's Disease
Study Type
Interventional

2. Study Status

Record Verification Date
December 2022
Overall Recruitment Status
Recruiting
Study Start Date
June 6, 2022 (Actual)
Primary Completion Date
June 30, 2024 (Anticipated)
Study Completion Date
June 30, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
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
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.

6. Conditions and Keywords

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

7. Study Design

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

8. Arms, Groups, and Interventions

Arm Title
Real tACS - Real tACS
Arm Type
Experimental
Arm Description
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).
Arm Title
Sham tACS - Real tACS
Arm Type
Sham Comparator
Arm Description
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).
Intervention Type
Device
Intervention Name(s)
40 Hz transcranial alternating current stimulation
Intervention Description
42 sessions of 40 Hz transcranial alternating current stimulation (5 days/week for 9 weeks)
Intervention Type
Device
Intervention Name(s)
Sham stimulation
Intervention Description
42 sessions of sham stimulation (5 days/week for 9 weeks)
Primary Outcome Measure Information:
Title
Safety of transcranial alternating current stimulation delivered at home
Description
Incidence of Treatment-Emergent Adverse Events as assessed by the incidence of adverse events graded from 1 (mild) to 5 (fatal).
Time Frame
Through study completion, at week 26
Title
Tolerability of transcranial alternating current stimulation delivered at home
Description
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%.
Time Frame
Through study completion, at week 26
Secondary Outcome Measure Information:
Title
Changes in Clinical Dementia Rating scale (CDR) sum of boxes
Description
CDR-SB scores range from 0 to 18, with higher scores indicating worse cog- nition and daily function.
Time Frame
Change from baseline to week 9 - 18 - 26
Title
Changes in Alzheimer's Disease Assessment Scale Cognitive Subscale (ADAS-Cog)13
Description
ADAS-Cog13 scores range from 0 to 85, with higher scores indicating a greater deficit.
Time Frame
Change from baseline to week 9 - 18 - 26
Title
Changes in Rey Auditory Verbal Learning Test scores
Description
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).
Time Frame
Change from baseline to week 9 - 18 - 26
Title
Changes in Face-Name Associative Memory Test (FNAT) scores
Description
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).
Time Frame
Change from baseline to week 9 - 18 - 26
Title
Changes in Face-Name Neuropsychiatric Inventory (NPI-Q)
Description
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).
Time Frame
Change from baseline to week 9 - 18 - 26
Title
Changes in Zarit Burden Interview (ZBI)
Description
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).
Time Frame
Change from baseline to week 9 - 18 - 26
Title
Changes in Caregiver Burden Inventory (CBI)
Description
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).
Time Frame
Change from baseline to week 9 - 18 - 26
Title
Change in SAI measurements
Description
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.
Time Frame
Change from baseline to week 9 - 18 - 26
Title
Change in EEG gamma power
Description
By using electroencephalography (EEG), the investigators will evaluate the change in gamma power.
Time Frame
Change from baseline to week 9 - 18 - 26
Title
Change in plasma NfL levels
Description
Changes in plasma neurofilament light (NfL) levels (pg/mL) will be evaluated.
Time Frame
Change from baseline to week 9 - 18 - 26
Title
Change in plasma GFAP levels
Description
Changes in plasma glial fibrillary acidic protein (GFAP) levels (pg/mL) will be evaluated.
Time Frame
Change from baseline to week 9 - 18 - 26
Title
Change in plasma amyloid beta1-40 levels
Description
Change in plasma amyloid beta1-40 levels (pg/mL) will be evaluated.
Time Frame
Change from baseline to week 9 - 18 - 26
Title
Change in plasma amyloid beta1-42 levels
Description
Change in plasma amyloid beta1-42 levels (pg/mL) will be evaluated.
Time Frame
Change from baseline to week 9 - 18 - 26
Title
Change in brain amyloid plaque burden
Description
Change in standardized uptake value ratio (SUVR) of amyloid placque burden evaluated with amyloid PET.
Time Frame
Change from baseline to week 9
Title
Change in resting state MRI connectivity
Description
Change in resting state magnetic resonance imaging connectivity (default mode network) both static and dynamic.
Time Frame
Change from baseline to week 9 - 18 - 26

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Barbara Borroni, MD
Phone
+39 030 3995631
Email
bborroni@unibs.it
First Name & Middle Initial & Last Name or Official Title & Degree
Alberto Benussi, MD
Phone
+39 030 3995631
Email
benussialberto@gmail.com
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Barbara Borroni, MD
Organizational Affiliation
Azienda Ospedaliera Spedali Civili, Brescia
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Alberto Benussi, MD
Organizational Affiliation
University or Brescia
Official's Role
Principal Investigator
Facility Information:
Facility Name
ASST Spedali Civili di Brescia
City
Brescia
State/Province
BS
ZIP/Postal Code
25123
Country
Italy
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Barbara Borroni, MD
Phone
+39 030 3995631
Email
bborroni@inwind.it
First Name & Middle Initial & Last Name & Degree
Alberto Benussi, MD
Phone
+39 030 3995631
Email
benussialberto@gmail.com
First Name & Middle Initial & Last Name & Degree
Barbara Borroni, MD
First Name & Middle Initial & Last Name & Degree
Alberto Benussi, MD

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
19400723
Citation
Fries P. Neuronal gamma-band synchronization as a fundamental process in cortical computation. Annu Rev Neurosci. 2009;32:209-24. doi: 10.1146/annurev.neuro.051508.135603.
Results Reference
background
PubMed Identifier
27929004
Citation
Iaccarino HF, Singer AC, Martorell AJ, Rudenko A, Gao F, Gillingham TZ, Mathys H, Seo J, Kritskiy O, Abdurrob F, Adaikkan C, Canter RG, Rueda R, Brown EN, Boyden ES, Tsai LH. Gamma frequency entrainment attenuates amyloid load and modifies microglia. Nature. 2016 Dec 7;540(7632):230-235. doi: 10.1038/nature20587. Erratum In: Nature. 2018 Oct;562(7725):E1.
Results Reference
background
PubMed Identifier
31076275
Citation
Adaikkan C, Middleton SJ, Marco A, Pao PC, Mathys H, Kim DN, Gao F, Young JZ, Suk HJ, Boyden ES, McHugh TJ, Tsai LH. Gamma Entrainment Binds Higher-Order Brain Regions and Offers Neuroprotection. Neuron. 2019 Jun 5;102(5):929-943.e8. doi: 10.1016/j.neuron.2019.04.011. Epub 2019 May 7.
Results Reference
background
PubMed Identifier
30879788
Citation
Martorell AJ, Paulson AL, Suk HJ, Abdurrob F, Drummond GT, Guan W, Young JZ, Kim DN, Kritskiy O, Barker SJ, Mangena V, Prince SM, Brown EN, Chung K, Boyden ES, Singer AC, Tsai LH. Multi-sensory Gamma Stimulation Ameliorates Alzheimer's-Associated Pathology and Improves Cognition. Cell. 2019 Apr 4;177(2):256-271.e22. doi: 10.1016/j.cell.2019.02.014. Epub 2019 Mar 14.
Results Reference
background
PubMed Identifier
23785325
Citation
Herrmann CS, Rach S, Neuling T, Struber D. Transcranial alternating current stimulation: a review of the underlying mechanisms and modulation of cognitive processes. Front Hum Neurosci. 2013 Jun 14;7:279. doi: 10.3389/fnhum.2013.00279. eCollection 2013.
Results Reference
background
PubMed Identifier
33762220
Citation
Benussi A, Cantoni V, Cotelli MS, Cotelli M, Brattini C, Datta A, Thomas C, Santarnecchi E, Pascual-Leone A, Borroni B. Exposure to gamma tACS in Alzheimer's disease: A randomized, double-blind, sham-controlled, crossover, pilot study. Brain Stimul. 2021 May-Jun;14(3):531-540. doi: 10.1016/j.brs.2021.03.007. Epub 2021 Mar 21.
Results Reference
background
PubMed Identifier
35607946
Citation
Benussi A, Cantoni V, Grassi M, Brechet L, Michel CM, Datta A, Thomas C, Gazzina S, Cotelli MS, Bianchi M, Premi E, Gadola Y, Cotelli M, Pengo M, Perrone F, Scolaro M, Archetti S, Solje E, Padovani A, Pascual-Leone A, Borroni B. Increasing Brain Gamma Activity Improves Episodic Memory and Restores Cholinergic Dysfunction in Alzheimer's Disease. Ann Neurol. 2022 Aug;92(2):322-334. doi: 10.1002/ana.26411. Epub 2022 Jun 6.
Results Reference
background

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

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