Transcranial Magnetic Stimulation for Alzheimer's Disease Treatment (TMSAD)

Intervention Based on Transcranial Magnetic Stimulation for Alzheimer's Disease Patients: Randomized Clinical Trial

Background: Alzheimer's disease is a major health problem in our society. To date, pharmacological treatments to reduce Alzheimer's disease symptoms have obtained poor results and there is a growing interest in finding non-pharmacological treatments for this impactful disease. Transcranial Magnetic Stimulation is a non-invasive tool which can induce changes in brain activity and long term modifications of impaired neural networks, and therefore holds promise as a clinical intervention.

Our overall goal is to study the benefit of targeting Transcranial Magnetic Stimulation based on the individual's unique functional connectivity (personalized targeting) instead of current non-individualized approaches. Specifically, the intermittent Theta Burst protocol will be used and changes in cognitive, functional, and emotional deficits in these patients will be evaluated. Functional brain connectivity changes induced by the TMS treatment will be also assessed.

Methods: A double blind randomized controlled trial will be conducted to assess the effects of TMS treatment immediately, one month, three months and six months after the end of the treatment in comparison to the baseline measurements. Forty-five patients with a diagnosis of Alzheimer's disease, will be randomly allocated (1:1:1) into experimental (active Transcranial Magnetic Stimulation), sham control group, or conventional intervention control group. Neuropsychological, functional, and emotional assessment will be conducted, as well as functional connectivity measures, in order to assess the effectiveness of the treatment.

Discussion: The investigators expect to demonstrate that personalized Transcranial Magnetic Stimulation intervention has measurable positive impact in cognitive and emotional functioning, functionality, and brain connectivity, thus representing a potential treatment for Alzheimer's disease.

Study Overview

• Status: Not yet recruiting
• Conditions: Alzheimer Disease
• Intervention / Treatment: Device: Active Transcranial Magnetic Stimulation; Device: Sham Transcranial Magnetic Stimulation

• Study Type: Interventional
• Enrollment (Anticipated): 45
• Phase: Not Applicable

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 58 years to 73 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Diagnosis of Alzheimer's disease according to the diagnostic criteria of the National Institute on Ageing and the Alzheimer's Association
• Ages between 60 and 75 years
• Mini Mental State Examination score between 20 and 26
• Global Deterioration Scale score of 3 or 4
• Functional independence for basic daily life activities (part C of the Blessed Scale equal or 0)
• Rosen Ischemia Scale less or equal to 4
• Able to read and write
• Stable medical and pharmacological state during the 3 consecutive months immediately before the start of the study
• Computed Tomography Scan and Magnetic Resonance Imaging in the last 12 months previous to the selection, compatible with the diagnosis of probable Alzheimer's disease in the subjects diagnosed
• Absence of clinically significant anomalies in the medical history or clinical laboratory results during the selection
• Screening analyses within normal range with the objective of detecting and excluding other causes of dementia in the last 12 months previous to selection. Laboratory values required in order to be considered within the normal range are as follows: complete blood count, thyroid hormones, T4, folic acid, vitamin B12, albumin, transaminase alanine, amino-transferase aspartate, gamma-glutamic transferase, sodium, potassium, urea, creatinine, glucose while fasting
• Being treated by Acetylcholinesterase Inhibitors
• Signed consent form, previously approved by the Research Ethics Committee

Exclusion Criteria:

• Knowledge of Spanish or Catalan after the age of 15
• Less than 4 years of schooling
• Intellectual deficiency (Premorbid Intelligence Quotient, vocabulary, less than 85)
• Not controlled medical conditions or severe mental disorders that may affect the Central Nervous System, including signs of increased intracranial pressure or intracranial lesions
• Presenting one or more vascular risks
• Medical conditions not controlled that may cause medical emergencies in case the produce convulsions (expel: cardiac malformations, cardiac arrhythmias, asthma, etc.)
• Medical history of convulsions, previous diagnosis of epilepsy, previous registry of abnormal electroencephalogram or family history of epilepsy
• Severe hearing problems or ringing in the ears (tinnitus)
• Severe loss of visual acuity
• Moderate or severe depression according to a score >11 (moderate depression) or 19 (severe depression) in the Geriatric Depression Scale
• Presence of tremors or motor control of the dominant upper extremity
• Being under pharmacological treatment with medications indicated in the security guidelines.
• Drug or alcohol consumption or history of abuse in the last 24 months prior to the study
• Implants of metal pieces in the brain (excluding dental fillings)
• Either of the following medical devices: pacemaker, implanted medication pumps, vagal nerve stimulators, deep cerebral stimulators, transcutaneous electrical stimulation units, ventriculus-peritoneal derivations, titanium plates, cochlear implants, aneurysm clips, etc…
• Negative response towards new technology
• Existence of any situation that may cause the subject, according to the principal researcher, not be an adequate candidate for the study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Experimental group; Transcranial Magnetic Stimulation + Conventional intervention	Device: Active Transcranial Magnetic Stimulation; The intervention consists of a 2-week treatment during which TMS will be applied for 10 days (every working day). The stimulation protocol will be intermittent TBS (iTBS). 600 pulses in each area will be applied at intervals of 2 seconds of stimulation and 8 seconds of rest; the total number of pulses per session will be 1200. The stimulation duration is 3 minutes and 12 seconds. This protocol allows the induction of long-term potentiation effects, promoting plasticity in the stimulated areas. To perform the stimulation a 70 mm, figure of 8-coil will be used. In order to precisely locate the stimulated areas a stereotactic image guidance will be used during the stimulation (Brainsight™ 2); Other Names: Magstim Super Rapid 2
Sham Comparator: Sham control group; Sham Transcranial Magnetic Stimulation + Conventional intervention	Device: Sham Transcranial Magnetic Stimulation; The Sham intervention will be carried out using the same stimulation protocol as in the active condition but with the coil rotated 90º to prevent the magnetic field inducing electrical activity in the cortex.; Other Names: Magstim Super Rapid 2
No Intervention: Non TMS Control group; Conventional intervention alone

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Cognitive improvement	Changes in cognitive functions will be assessed through a Neuropsychological Batery	Baseline and 1 month, 3 months and 6 months after the end of the treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Functional capacity changes_1	Functional capacity will be assessed through the Functional Assessment Questionnaire (FAQ)	Baseline and 1 month, 3 months and 6 months after the end of the treatment
Functional capacity changes_2	Functional capacity will be assessed through the UCSD Performance-Based Skills Assessment (UPSA)	Baseline and 1 month, 3 months and 6 months after the end of the treatment
Mood changes	Mood changes will be assessed through the Hospital Anxiety and Depression Scale (HAD)	Baseline and 1 month, 3 months and 6 months after the end of the treatment
Changes in brain connectivity	Brain connectivity will be assessed through the registry of brain activity in the resting state Magnetic Resonance Imaging.	3 days after the end of the treatment

Collaborators and Investigators

• Sponsor: Universitat Oberta de Catalunya
• Collaborators: Consorci Sanitari de Terrassa

Publications and helpful links

General Publications

• Marron EM, Viejo-Sobera R, Quintana M, Redolar-Ripoll D, Rodriguez D, Garolera M. Transcranial magnetic stimulation intervention in Alzheimer's disease: a research proposal for a randomized controlled trial. BMC Res Notes. 2018 Sep 5;11(1):648. doi: 10.1186/s13104-018-3757-z.

Study record dates

Study Major Dates

• Study Start (Anticipated): November 1, 2023
• Primary Completion (Anticipated): September 1, 2024
• Study Completion (Anticipated): December 1, 2024

Study Registration Dates

• First Submitted: April 1, 2017
• First Submitted That Met QC Criteria: April 18, 2017
• First Posted (Actual): April 19, 2017

Study Record Updates

• Last Update Posted (Actual): November 9, 2022
• Last Update Submitted That Met QC Criteria: November 8, 2022
• Last Verified: November 1, 2022

More Information

Terms related to this study

• Keywords: Transcranial Magnetic Stimulation; Non invasive brain stimulation; Brain connectivity; Theta Burst Protocol; Dorsolateral prefrontal cortex; Parietal cortex
• Additional Relevant MeSH Terms: Mental Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurocognitive Disorders; Neurodegenerative Diseases; Dementia; Tauopathies; Alzheimer Disease
• Other Study ID Numbers: UOCatalunya

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No