Clinical trial NCT05643326: At Home Gamma tACS in Alzheimer's Disease (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
Overall status: COMPLETED
Phase: NA
Conditions: Alzheimer Disease
Lead sponsor: Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia
Sponsor class: OTHER
First posted: 2022-12-08
Enrollment: 53
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Safety of transcranial alternating current stimulation delivered at home
timeFrame: Through study completion, at week 24
measure: Tolerability of transcranial alternating current stimulation delivered at home
timeFrame: Through study completion, at week 24
measure: Changes in Clinical Dementia Rating scale (CDR) sum of boxes
timeFrame: Difference between treatments (real and sham) at week 8
measure: Changes in Alzheimer's Disease Assessment Scale Cognitive Subscale (ADAS-Cog)13
timeFrame: Difference between treatments (real and sham) at week 8
measure: Changes in Face-Name Associative Memory Test (FNAT) scores
timeFrame: Difference between treatments (real and sham) at week 8
measure: Changes in Alzheimer's Disease Assessment Scale Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL)
timeFrame: Difference between treatments (real and sham) at week 8
Secondary outcomes:
measure: Changes in Clinical Dementia Rating scale (CDR) sum of boxes
timeFrame: Change from baseline to week 8 - 16 - 24
measure: Changes in Alzheimer's Disease Assessment Scale Cognitive Subscale (ADAS-Cog)13
timeFrame: Change from baseline to week 8 - 16 - 24
measure: Changes in Rey Auditory Verbal Learning Test scores
timeFrame: Change from baseline to week 8 - 16 - 24
measure: Changes in Face-Name Associative Memory Test (FNAT) scores
timeFrame: Change from baseline to week 8 - 16 - 24
measure: Changes in the Neuropsychiatric Inventory (NPI-Q)
timeFrame: Change from baseline to week 8 - 16 - 24
measure: Changes in Caregiver Burden Inventory (CBI)
timeFrame: Change from baseline to week 8 - 16 - 24
measure: Changes in Alzheimer's Disease Assessment Scale Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL)
timeFrame: Change from baseline to week 8 - 16 - 24
measure: Change in SAI measurements
timeFrame: Change from baseline to week 8 - 16 - 24
measure: Change in EEG gamma power
timeFrame: Change from baseline to week 8 - 16 - 24
measure: Change in plasma NfL levels
timeFrame: Change from baseline to week 8 - 16 - 24
measure: Change in plasma GFAP levels
timeFrame: Change from baseline to week 8 - 16 - 24
measure: Change in plasma amyloid beta1-40 levels
timeFrame: Change from baseline to week 8 - 16 - 24
measure: Change in plasma amyloid beta1-42 levels
timeFrame: Change from baseline to week 8 - 16 - 24
measure: Change in plasma pTau217
timeFrame: Change from baseline to week 8 - 16 - 24
measure: Change in resting state MRI connectivity
timeFrame: Change from baseline to week 8
measure: Change in plasma TMT part B scores
timeFrame: Change from baseline to week 8 - 16 - 24
measure: Changes in semantic fluency task
timeFrame: Change from baseline to week 8 - 16 - 24
Other outcomes:
Locations:
city: Brescia
country: Italy
facility: ASST Spedali Civili di Brescia
state: BS
Study officials:
affiliation: Azienda Ospedaliera Spedali Civili, Brescia
name: Barbara Borroni, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University or Brescia
name: Alberto Benussi, MD
role: PRINCIPAL_INVESTIGATOR
References:
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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.
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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.
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.