Prediction of Effectiveness of rTMS Application in Alzheimer's Patients (PRIM-A)

Prediction of Cognitive, Neurotrophic, Anti-Inflammatory, and Antioxidant Effectiveness of rTMS Application in Alzheimer's Patients

Since pharmacological methods are insufficient in the treatment processes of Alzheimer's disease, non-pharmacological methods such as Transcranial Magnetic Stimulation (TMS) have started to be tried as a treatment option as in other neurological and psychiatric diseases. Repeated (rTMS) offers a potential treatment pathway for neurological and psychiatric illnesses. rTMS benefit rate may vary depending on many factors such as the region where it is applied, the progression and the disease degree. The possible effects of TMS on Alzheimer's pathophysiology and modification of disease process (neuroprotective, anti-inflammatory and antioxidant) will also be revealed through blood samples taken from patients before and after treatment. These approaches also constitute the original value of our study.

Study Overview

• Status: Recruiting
• Conditions: Alzheimer Disease
• Intervention / Treatment: Device: Repetetive Transcranial Magnetic Stimulation

Detailed Description

Since pharmacological methods are insufficient in the treatment processes of Alzheimer's disease, non-pharmacological methods such as Transcranial Magnetic Stimulation (TMS) have started to be tried as a treatment option as in other neurological and psychiatric diseases. Repeated (rTMS) offers a potential treatment pathway for neurological and psychiatric illnesses. rTMS benefit rate may vary depending on many factors such as the region where it is applied, the progression and the disease degree. This study aim is to predict the benefit rate to be obtained from the treatment by using various evaluation parameters before starting rTMS treatment. The possible effects of TMS on Alzheimer's pathophysiology and modification of disease process (neuroprotective, anti-inflammatory and antioxidant) will also be revealed through blood samples taken from patients before and after treatment. These approaches also constitute the original value of our study.

In our project, 20 people will be included in the study and control groups and electroencephalography (EEG) and TMS will be used together in the study. Before rTMS treatment, resting EEG data will be taken for 5 minutes, eyes open and closed. At the end of all these procedures, rTMS treatment will be started, which will take 5 days. The treatment will consist of two sessions per day with a 20 Hz stimulating protocol, 1500 beats to right-left DLPFC, and totaly 3000 beats. EEG recordings will be taken again from all patients one week after the treatment.

Changes in the cognitive functions of Alzheimer's patients will be made through the neuropsychometric test battery taken before and after rTMS. With the analysis of neuropsychometric data, the study group will be divided into two subgroups that benefit from TMS and those who do not. In addition, EEG data obtained before and after-TMS will be compared with power spectrum, coherence, functional connectivity and graph methods in both the study and control groups, and information about the electrophysiological effects of TMS will be obtained.

Blood samples of the patients before and after rTMS will be taken and the changes in the metabolites given below will be compared: Brain Derived Neurotrophic Factor, Glial Based Neurotrophic Factor, Total Oxidant Level, Total Antioxidant Level, Oxidative Stress Index, Total Thiol, Native Thiol, Disulfide, Exosome, Inflammation Biomarkers (interleukin 1 Beta, interleukin 6, Tumor Necrosis Alpha, Interferon gamma, Nuclear factor kappa ß), Albumin Globulin ratio, Omega 6 and Omega 3. Thus, rTMS has possible neuroprotective, anti-inflammatory and antioxidant effects, consequently modifying the disease process. Additional information will be obtained about.

• Study Type: Interventional
• Enrollment (Estimated): 40
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Lutfu Hanoglu, Prof. DR. MD; Phone Number: +90 444 8 544; Email: lhanoglu@kure.com.tr
• Study Contact Backup: Name: Cennet Sena Parlatan, PhD Cand; Phone Number: 05077799164; Email: cennetsenaparlatan@gmail.com

Study Locations

• Turkey
  • Istanbul, Turkey, 34214
    • Recruiting
    • Medipol University Hospital
    • Contact: Lutfu Hanoglu, MD, PhD; Phone Number: 0090 212 460 70 30; Email: lhanoglu@kure.com.tr
    • Principal Investigator: Lutfu Hanoglu, MD, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Have been diagnosed with clinical Alzheimer's Disease in accordance with the NINCDS-ADRDA diagnostic criteria
• >55 years old
• Clinical Dementia Rating Scale (CDR) score in the 1-2 range
• Not having any other disease that affects their cognitive functions
• Volunteer to participate in the study

Exclusion Criteria:

• Participant or relative does not give consent
• The patient's inability to participate in the entire study procedure (eg living in another city)
• The patient's history of head trauma with alcohol/substance abuse
• Presence of severe stroke and other neurological sequelae disease in the participant
• Presence of a metal implant on the head or having a pacemaker and contraindications for other TMS applications During the study or 1 month before, having/been receiving/receiving an investigational drug targeting Alzheimer's disease or neuromodulation treatment such as tDCS and TMS, other than standard treatment for AD symptom control such as acetylcholine esterase and memantine, with the potential to affect the study

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Sham Comparator: Sham; The same treatment procedures will be applied to the control group with a sham coil.	Device: Repetetive Transcranial Magnetic Stimulation; .Power Mag TMS device will be used throughout the study, and the excitations will be made with the help of an 8 shaped coil (diameter: 70 mm) with internal cooling. The right-left DLPFC, which is the application area, will be determined with the help of the primary motor hand area and the 10/20 EEG system. A resting state EEG (eyes open-closed) will be taken in the Faraday cage. The same procedures will be done with the sham coil in the control group.; Other Names: Electroensefolography
Experimental: Interventional; Power Mag TMS device will be used throughout the study, and the excitations will be made with the help of an 8 shaped coil (diameter: 70 mm) with internal cooling. The right-left DLPFC, which is the application area, will be determined with the help of the primary motor hand area and the 10/20 EEG system. A resting state EEG (eyes open-closed) will be taken i in the Faraday cage.	Device: Repetetive Transcranial Magnetic Stimulation; .Power Mag TMS device will be used throughout the study, and the excitations will be made with the help of an 8 shaped coil (diameter: 70 mm) with internal cooling. The right-left DLPFC, which is the application area, will be determined with the help of the primary motor hand area and the 10/20 EEG system. A resting state EEG (eyes open-closed) will be taken in the Faraday cage. The same procedures will be done with the sham coil in the control group.; Other Names: Electroensefolography

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The Mini Mental State Examination	Cognitive Neuropsychological Test Score	Changes Before Treatment and 1 month after treatment
Neuropsychiatric Inventory	Cognitive Neuropsychological Test Score	Changes Before Treatment and 1 month after treatment
Alzheimer's Disease Assessment Scale	Cognitive Neuropsychological Test Score	Changes Before Treatment and 1 month after treatment
ADSL	Cognitive Neuropsychological Test Score	Changes Before Treatment and 1 month after treatment
Geriatric Depression Scale	Cognitive Neuropsychological Test Score	Changes Before Treatment and 1 month after treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Blood samples ELISA analyses	BDNF:measured spectrophotometrically with commercially purchased ELISA kits. GDNF:measured spectrophotometrically with commercially purchased ELISA kits. Exosome: measured spectrophotometrically with commercially available ELISA kits. Anti-inflammatory Cytokines: IL-1β, IL-6, TNF-α, IFNy, NF-kβ values will be measured spectrophotometrically with commercially purchased ELISA kits.	Changes Before Treatment and 1 month after treatment
Blood samples analyses	OSI:TOS and TAS will be measured by photometric methods. OSI will be found by mathematical calculation. Total thiol and native thiol concentrations are measured spectrophotometrically in separate solutions prepared for the determination of the thiol-disulfite ratio, which is another indicator of oxidative stress, and the amount of disulfide is determined according to the mathematical ratio between them. Albumin Globulin Ratio:measured by electrophoresis method and albumin globulin ratio will be determined. Omega 6/3 Levels:determined by commercially purchased lipid mediators.	Changes Before Treatment and 1 month after treatment
Inflammatory Biomarker analyses	Inflammatory parameters IL-1β, IL-6 and TNF-α will be measured IL-1β, IL-6 and TNF-α levels will be measured photometrically with commercially available ELISA kits.	Changes Before Treatment and 1 month after treatment
Oxidative Stress Biomarker analyses	TAS, TOS, TT and NT levels of oxidative stress parameters in blood samples taken from AD patients will be measured. TAS, TOS, TT, NT levels of blood samples taken will be measured by photometric method with kits to be purchased commercially. The oxidative stress index (OSI) will be found as TOS/TAS, and the amount of dynamic disulfide bonds will be found by determining half of the difference between the TT and NT groups.	Changes Before Treatment and 1 month after treatment
Evaluation of Fatty Acid Profile Analysis with GC-MS	Fatty acids comprising more than 95% of the fatty acids detectable in plasma will be measured. Tetradecanoic acid,9(Z)-Tetradecenoic acid,Hexadecanoic acid,9(Z)-Hexadecenoic acid,9(E)-Hexadecenoic acid,Octadecanoic acid,9(Z)-Octadecenoic acid,Methyl 9(E)- Octadecenoate,11(Z)-Octadecenoic acid,Methyl 11(E)- Octadecenoate,Methyl 6(Z)- Octadecenoate,9(Z),12(Z)- Octadecadienoic acid,9(E),12(E)- Octadecadienoic acid,9(Z),12(Z),15(Z)- Octadecatrienoic acid, 6(Z),9(Z),12(Z)- Octadecatrienoic acid,Eicosanoic acid,8(Z),11(Z),14(Z)- Eicosatrienoic acid, 5(Z),8(Z),11(Z),14(Z)-Eicosatetraenoic acid, 11(Z)-Eicosenoic acid, 11(Z),14(Z)- Eicosadienoic acid, 5(Z),8(Z),11(Z),14(Z),17(Z)- Eicosapentaenoic acid, Docosanoic acid, 13(Z)-Docosenoic acid 4(Z),7(Z),10(Z),13(Z),16(Z),19(Z)- Docosahexaenoic acid 7(Z),10(Z),13(Z),16(Z)-Docosatetraenoic acid 7(Z),10(Z),13(Z),16(Z),19(Z)- Docosapentaenoic acid 4(Z),7(Z),10(Z),13(Z),16(Z)- Docosapentaenoic acid Tetracosanoic acid 15(Z)-Tetracosenoic acid	Changes Before Treatment and 1 month after treatment
Metabolomics Analysis by Liquid Chromatography-Mass Spectrometer/Mass Spectrometer (LC-MS/MS)	The 41 amino acids to look for by LC-MS/MS are: 1-Methylhistidine; 2-Aminoadipic Acid; 3-Aminoisobutyric Acid; 3-Methylhistidine; 4-Hydroxyproline; 5-Hydroxylysine; Alanine; Alloisoleucine; Anserine; Arginine; Argininosuccinic Acid; Asparagine; β-Alanine; Carnosine; Citrulline; Cystine; Cystathionine; Ethanolamine; Gamma-Aminobutyric Acid; Glutamine; Glutamic Acid; Histidine; Homocitrulline; Isoleucine; Leucine; Lysine; Methionine; Norvaline; O-Phosphorylethanolamine; O-Phosphoserine; Ornithine; Phenylanalanine; Proline; Sarcosine; Serine; Taurine; Threonine; Trans-4-Hydroxyproline; Tryptophan; Tyrosine; Valine	Changes Before Treatment and 1 month after treatment
EEG Power Spectrum Analysis	EEG data will be separated into one-second epochs after they are cleared of noise. Power spectrums of these data will be obtained in the delta, theta, alpha, beta and gamma frequency bands. Each epoch will be analyzed by Fast Fourier Transform (FFT, Fast Fourier Transform) with 10% Hanning window, then power spectrum analysis will be performed, giving the frequency values for each electrode by averaging all FFTs. Maximum peaks will be determined in the delta (0.5-3.5 Hz), theta (4-7 Hz), alpha (8-13 Hz), beta (15-28 Hz) and gamma (28-48 Hz) frequency bands. these values will be used in statistical analysis for each person and electrode.	Changes Before Treatment and 1 month after treatment
EEG Coherence Analysis	Coherence measurements at delta, theta, alpha, beta and gamma frequencies can be analyzed for either intra-hemispheric electrode connections or inter-hemipheric electrode connections.Coherence values take values between 0-1. Values close to 0 indicate that there is no connection at the determined frequency between the two calculated electrode regions, while values close to 1 indicate a high coupling between the two electrode regions. Coherence values will be calculated with the Brain Vision Analyzer program using the formula below.The data obtained during memory and visualization will be separated into one-second epochs after they are cleared of noise.Power spectrums of these data will be obtained in the delta, theta, alpha, beta and gamma frequency bands. Each epoch will be analyzed by Fast Fourier Transform with 10% Hanning window.Then, these data will be calculated for all possible electrode pairs using the brain vision analysis program with the formula given below.	Changes Before Treatment and 1 month after treatment

Collaborators and Investigators

• Sponsor: Istanbul Medipol University Hospital
• Collaborators: Bezmialem Vakif University; Saglik Bilimleri Universitesi
• Investigators: Principal Investigator: Lutfu Hanoglu, Prof. DR. MD, Medipol University

Study record dates

Study Major Dates

• Study Start (Actual): February 16, 2022
• Primary Completion (Estimated): May 15, 2025
• Study Completion (Estimated): December 30, 2025

Study Registration Dates

• First Submitted: June 2, 2023
• First Submitted That Met QC Criteria: July 27, 2023
• First Posted (Actual): August 4, 2023

Study Record Updates

• Last Update Posted (Actual): May 2, 2025
• Last Update Submitted That Met QC Criteria: April 30, 2025
• Last Verified: April 1, 2025

More Information

Terms related to this study

• Keywords: Alzheimer's Disease; TMS-EEG; Anti-inflammatory-neuroprotective-antioxidant effect
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Mental Disorders; Neurocognitive Disorders; Dementia; Tauopathies; Neurodegenerative Diseases; Alzheimer Disease
• Other Study ID Numbers: 221S749

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Data will not be shared due to ethical reasons

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