xml: <clinical_study>
    <!-- This xml conforms to an XML Schema at:
      https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
    <required_header>
      <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
      <link_text>Link to the current ClinicalTrials.gov record.</link_text>
      <url>https://clinicaltrials.gov/ct2/show/NCT05977088</url>
    </required_header>
    <id_info>
      <org_study_id>221S749</org_study_id>
      <nct_id>NCT05977088</nct_id>
    </id_info>
    <brief_title>Prediction of Effectiveness of rTMS Application in Alzheimer's Patients</brief_title>
    <official_title>Prediction of Cognitive, Neurotrophic, Anti-Inflammatory, and Antioxidant Effectiveness of rTMS Application in Alzheimer's Patients by Combination of Test-Dose TMS and EEG</official_title>
    <sponsors>
      <lead_sponsor>
        <agency>Istanbul Medipol University Hospital</agency>
        <agency_class>Other</agency_class>
      </lead_sponsor>
      <collaborator>
        <agency>Bezmialem Vakif University</agency>
        <agency_class>Other</agency_class>
      </collaborator>
      <collaborator>
        <agency>Saglik Bilimleri Universitesi</agency>
        <agency_class>Other</agency_class>
      </collaborator>
    </sponsors>
    <source>Istanbul Medipol University Hospital</source>
    <oversight_info>
      <has_dmc>No</has_dmc>
      <is_fda_regulated_drug>No</is_fda_regulated_drug>
      <is_fda_regulated_device>No</is_fda_regulated_device>
    </oversight_info>
    <brief_summary>
      <textblock>
        Since pharmacological methods are insufficient in the treatment processes of Alzheimer's&#xD;
        disease, non-pharmacological methods such as Transcranial Magnetic Stimulation (TMS) have&#xD;
        started to be tried as a treatment option as in other neurological and psychiatric diseases.&#xD;
        Repeated (rTMS) offers a potential treatment pathway for neurological and psychiatric&#xD;
        illnesses. rTMS benefit rate may vary depending on many factors such as the region where it&#xD;
        is applied, the progression and the disease degree. This study aim is to predict the benefit&#xD;
        rate to be obtained from the treatment by using various evaluation parameters before starting&#xD;
        rTMS treatment. Another goal is to develop a personalized TMS treatment protocol based on the&#xD;
        effect of Test Dose TMS on EEG and change in brain networks that can be viewed from EEG data&#xD;
        generally before and after rTMS treatment. The possible effects of TMS on Alzheimer's&#xD;
        pathophysiology and modification of disease process (neuroprotective, anti-inflammatory and&#xD;
        antioxidant) will also be revealed through blood samples taken from patients before and after&#xD;
        treatment. These approaches also constitute the original value of our study.&#xD;
      </textblock>
    </brief_summary>
    <detailed_description>
      <textblock>
        Since pharmacological methods are insufficient in the treatment processes of Alzheimer's&#xD;
        disease, non-pharmacological methods such as Transcranial Magnetic Stimulation (TMS) have&#xD;
        started to be tried as a treatment option as in other neurological and psychiatric diseases.&#xD;
        Repeated (rTMS) offers a potential treatment pathway for neurological and psychiatric&#xD;
        illnesses. rTMS benefit rate may vary depending on many factors such as the region where it&#xD;
        is applied, the progression and the disease degree. This study aim is to predict the benefit&#xD;
        rate to be obtained from the treatment by using various evaluation parameters before starting&#xD;
        rTMS treatment. Another goal is to develop a personalized TMS treatment protocol based on the&#xD;
        effect of Test Dose TMS on EEG and change in brain networks that can be viewed from EEG data&#xD;
        generally before and after rTMS treatment. The possible effects of TMS on Alzheimer's&#xD;
        pathophysiology and modification of disease process (neuroprotective, anti-inflammatory and&#xD;
        antioxidant) will also be revealed through blood samples taken from patients before and after&#xD;
        treatment. These approaches also constitute the original value of our study.&#xD;
  &#xD;
        In our project, 20 people will be included in the study and control groups and&#xD;
        electroencephalography (EEG) and TMS will be used together in the study. Before rTMS&#xD;
        treatment, resting EEG data will be taken for 5 minutes, eyes open and closed. After then,&#xD;
        Test Dose TMS of 150 beats at 20 Hz will be applied to left dorsolateral prefrontal cortex.&#xD;
        Immediately after this Test Dose rTMS, the patient's resting state EEG data will be taken&#xD;
        again. At the end of all these procedures, rTMS treatment will be started, which will take 5&#xD;
        days. The treatment will consist of two sessions per day with a 20 Hz stimulating protocol,&#xD;
        1500 beats to right-left DLPFC, and totaly 3000 beats. EEG recordings will be taken again&#xD;
        from all patients one week after the treatment.&#xD;
  &#xD;
        Changes in the cognitive functions of Alzheimer's patients will be made through the&#xD;
        neuropsychometric test battery taken before and after rTMS. With the analysis of&#xD;
        neuropsychometric data, the study group will be divided into two subgroups that benefit from&#xD;
        TMS and those who do not, the effect of Test Dose TMS on EEG will be investigated, the&#xD;
        algorithm that predicts individuals who will benefit from TMS through pre-TMS EEG data and&#xD;
        Test Dose TMS-EEG data will be investigated and The effect of TMS treatment on EEG will be&#xD;
        investigated. Therefore, the prediction algorithm will open the door to personalized&#xD;
        treatment protocol. In addition, EEG data obtained before and after-TMS will be compared with&#xD;
        power spectrum, coherence, functional connectivity and graph methods in both the study and&#xD;
        control groups, and information about the electrophysiological effects of TMS will be&#xD;
        obtained.&#xD;
  &#xD;
        Blood samples of the patients before and after rTMS will be taken and the changes in the&#xD;
        metabolites given below will be compared: Brain Derived Neurotrophic Factor, Glial Based&#xD;
        Neurotrophic Factor, Total Oxidant Level, Total Antioxidant Level, Oxidative Stress Index,&#xD;
        Total Thiol, Native Thiol, Disulfide, Exosome, Inflammation Biomarkers (interleukin 1 Beta,&#xD;
        interleukin 6, Tumor Necrosis Alpha, Interferon gamma, Nuclear factor kappa ß), Albumin&#xD;
        Globulin ratio, Omega 6 and Omega 3. Thus, rTMS has possible neuroprotective,&#xD;
        anti-inflammatory and antioxidant effects, consequently modifying the disease process.&#xD;
        Additional information will be obtained about.&#xD;
  &#xD;
        Within the scope of the project, a workshop, sharing of study results in&#xD;
        national-international congresses, a patent application originating from algorithm&#xD;
        production, production of 3 graduate students' thesis and at least 3 scientific articles will&#xD;
        be produced. In addition, the investigators anticipate that TMS prevalence will increase&#xD;
        during the treatment process of Alzheimer's patients, and the socio-economic burden caused by&#xD;
        this disease will be reduced.&#xD;
      </textblock>
    </detailed_description>
    <overall_status>Recruiting</overall_status>
    <start_date type="Actual">February 16, 2022</start_date>
    <completion_date type="Anticipated">May 15, 2025</completion_date>
    <primary_completion_date type="Anticipated">May 15, 2025</primary_completion_date>
    <phase>N/A</phase>
    <study_type>Interventional</study_type>
    <has_expanded_access>No</has_expanded_access>
    <study_design_info>
      <allocation>Randomized</allocation>
      <intervention_model>Parallel Assignment</intervention_model>
      <primary_purpose>Diagnostic</primary_purpose>
      <masking>Single (Participant)</masking>
    </study_design_info>
    <primary_outcome>
      <measure>The Mini Mental State Examination</measure>
      <time_frame>Changes Before Treatment and 1 month after treatment</time_frame>
      <description>Cognitive Neuropsychological Test Score</description>
    </primary_outcome>
    <primary_outcome>
      <measure>Neuropsychiatric Inventory</measure>
      <time_frame>Changes Before Treatment and 1 month after treatment</time_frame>
      <description>Cognitive Neuropsychological Test Score</description>
    </primary_outcome>
    <primary_outcome>
      <measure>Alzheimer's Disease Assessment Scale</measure>
      <time_frame>Changes Before Treatment and 1 month after treatment</time_frame>
      <description>Cognitive Neuropsychological Test Score</description>
    </primary_outcome>
    <primary_outcome>
      <measure>ADSL</measure>
      <time_frame>Changes Before Treatment and 1 month after treatment</time_frame>
      <description>Cognitive Neuropsychological Test Score</description>
    </primary_outcome>
    <primary_outcome>
      <measure>Geriatric Depression Scale</measure>
      <time_frame>Changes Before Treatment and 1 month after treatment</time_frame>
      <description>Cognitive Neuropsychological Test Score</description>
    </primary_outcome>
    <secondary_outcome>
      <measure>Blood samples ELISA analyses</measure>
      <time_frame>Changes Before Treatment and 1 month after treatment</time_frame>
      <description>BDNF:measured spectrophotometrically with commercially purchased ELISA kits. GDNF:measured spectrophotometrically with commercially purchased ELISA kits. Exosome: measured spectrophotometrically with commercially available ELISA kits.&#xD;
  Anti-inflammatory Cytokines: IL-1β, IL-6, TNF-α, IFNy, NF-kβ values will be measured spectrophotometrically with commercially purchased ELISA kits.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Blood samples analyses</measure>
      <time_frame>Changes Before Treatment and 1 month after treatment</time_frame>
      <description>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.&#xD;
  Albumin Globulin Ratio:measured by electrophoresis method and albumin globulin ratio will be determined.&#xD;
  Omega 6/3 Levels:determined by commercially purchased lipid mediators.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Inflammatory Biomarker analyses</measure>
      <time_frame>Changes Before Treatment and 1 month after treatment</time_frame>
      <description>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.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Oxidative Stress Biomarker analyses</measure>
      <time_frame>Changes Before Treatment and 1 month after treatment</time_frame>
      <description>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.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Evaluation of Fatty Acid Profile Analysis with GC-MS</measure>
      <time_frame>Changes Before Treatment and 1 month after treatment</time_frame>
      <description>Fatty acids comprising more than 95% of the fatty acids detectable in plasma will be measured.&#xD;
  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</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Metabolomics Analysis by Liquid Chromatography-Mass Spectrometer/Mass Spectrometer (LC-MS/MS)</measure>
      <time_frame>Changes Before Treatment and 1 month after treatment</time_frame>
      <description>The 41 amino acids to look for by LC-MS/MS are:&#xD;
  1-Methylhistidine&#xD;
  2-Aminoadipic Acid&#xD;
  3-Aminoisobutyric Acid&#xD;
  3-Methylhistidine&#xD;
  4-Hydroxyproline&#xD;
  5-Hydroxylysine&#xD;
  Alanine&#xD;
  Alloisoleucine&#xD;
  Anserine&#xD;
  Arginine&#xD;
  Argininosuccinic Acid&#xD;
  Asparagine&#xD;
  β-Alanine&#xD;
  Carnosine&#xD;
  Citrulline&#xD;
  Cystine&#xD;
  Cystathionine&#xD;
  Ethanolamine&#xD;
  Gamma-Aminobutyric Acid&#xD;
  Glutamine&#xD;
  Glutamic Acid&#xD;
  Histidine&#xD;
  Homocitrulline&#xD;
  Isoleucine&#xD;
  Leucine&#xD;
  Lysine&#xD;
  Methionine&#xD;
  Norvaline&#xD;
  O-Phosphorylethanolamine&#xD;
  O-Phosphoserine&#xD;
  Ornithine&#xD;
  Phenylanalanine&#xD;
  Proline&#xD;
  Sarcosine&#xD;
  Serine&#xD;
  Taurine&#xD;
  Threonine&#xD;
  Trans-4-Hydroxyproline&#xD;
  Tryptophan&#xD;
  Tyrosine&#xD;
  Valine</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>EEG Power Spectrum Analysis</measure>
      <time_frame>Changes Before Treatment and 1 month after treatment</time_frame>
      <description>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.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>EEG Coherence Analysis</measure>
      <time_frame>Changes Before Treatment and 1 month after treatment</time_frame>
      <description>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.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>EEG functional connectivity analysis</measure>
      <time_frame>Changes Before Treatment and 1 month after treatment</time_frame>
      <description>eLORETA software will be used for functional connectivity analysis. sLORETA /eLORETA is an online free software developed by Roberto Pascual-Marqui and his team (http://www.uzh.ch/keyinst/loreta.htm). eLORETA is an algorithm developed to solve the inverse problem and it does not contain localization bias even in the presence of noise (Pascual-Marqui, 2007). In this software, resting state data with eyes closed, separated into 2 second epochs, whose artifacts are cleaned by preprocessing, will be used. The relevant areas to be analyzed in the cortical plane and the relevant frequency band gaps will be determined. The time series containing the eLORETA current source density obtained from these areas will be calculated and a &quot;lagged linear coherence&quot; matrix will be created to be applied in graph theory (Vecchio et al., 2014). &quot;Lagged linear coherence&quot; will give correct physiological connectivity unaffected by volume conduction and low spatial resolution (Pascual-Marqui et al., 2011).</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>EEG Analysis by Machine Learning</measure>
      <time_frame>Changes Before Treatment and 1 month after treatment</time_frame>
      <description>The machine learning method was created based on the current experimental design and the planned number of patients. After the data is cleared and ready for analysis, the differences in the EEG signals of the patients who benefited from rTMS after the Test Dose TMS from the EEG signals after the Test Dose TMS of the patients who did not benefit will be revealed by a classification method. For this purpose, it is planned to implement the Support Vector Machines (SVM) method. The DVM method is the most suitable for our data and the project purpose among the machine learning methods with its high classification success in large-sized data that is difficult to parse.</description>
    </secondary_outcome>
    <number_of_arms>2</number_of_arms>
    <enrollment type="Anticipated">40</enrollment>
    <condition>Alzheimer Disease</condition>
    <arm_group>
      <arm_group_label>Interventional</arm_group_label>
      <arm_group_type>Experimental</arm_group_type>
      <description>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.&#xD;
  Patients will be given two stimulations (pulse duration=3.5 sec, interval between beats=45 sec) consisting of only 75 beats, 100% of the cap threshold value compatible with the magnetic field TMS determined just before the rTMS routine application, and a total of 150 pulses of Test Dose TMS will be applied. A resting state EEG (eyes open-closed) will be taken immediately after (max. 2 minutes later) in the Faraday cage.</description>
    </arm_group>
    <arm_group>
      <arm_group_label>Sham</arm_group_label>
      <arm_group_type>Sham Comparator</arm_group_type>
      <description>The same treatment procedures will be applied to the control group with a sham coil.</description>
    </arm_group>
    <intervention>
      <intervention_type>Device</intervention_type>
      <intervention_name>Repetetive Transcranial Magnetic Stimulation</intervention_name>
      <description>.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.&#xD;
  Patients will be given two stimulations (pulse duration=3.5 sec, interval between beats=45 sec) consisting of only 75 beats, 100% of the cap threshold value compatible with the magnetic field TMS determined just before the rTMS routine application, and a total of 150 pulses of Test Dose TMS will be applied. A resting state EEG (eyes open-closed) will be taken immediately after (max. 2 minutes later) in the Faraday cage. The same procedures will be done with the sham coil in the control group.</description>
      <arm_group_label>Interventional</arm_group_label>
      <arm_group_label>Sham</arm_group_label>
      <other_name>Electroensefolography</other_name>
    </intervention>
    <eligibility>
      <criteria>
        <textblock>
          Inclusion Criteria:&#xD;
  &#xD;
            -  Have been diagnosed with clinical Alzheimer's Disease in accordance with the&#xD;
               NINCDS-ADRDA diagnostic criteria&#xD;
  &#xD;
            -  &gt;55 years old&#xD;
  &#xD;
            -  Clinical Dementia Rating Scale (CDR) score in the 1-2 range&#xD;
  &#xD;
            -  Not having any other disease that affects their cognitive functions&#xD;
  &#xD;
            -  Volunteer to participate in the study&#xD;
  &#xD;
          Exclusion Criteria:&#xD;
  &#xD;
            -  Participant or relative does not give consent&#xD;
  &#xD;
            -  The patient's inability to participate in the entire study procedure (eg living in&#xD;
               another city)&#xD;
  &#xD;
            -  The patient's history of head trauma with alcohol/substance abuse&#xD;
  &#xD;
            -  Presence of severe stroke and other neurological sequelae disease in the participant&#xD;
  &#xD;
            -  Presence of a metal implant on the head or having a pacemaker and contraindications&#xD;
               for other TMS applications During the study or 1 month before, having/been&#xD;
               receiving/receiving an investigational drug targeting Alzheimer's disease or&#xD;
               neuromodulation treatment such as tDCS and TMS, other than standard treatment for AD&#xD;
               symptom control such as acetylcholine esterase and memantine, with the potential to&#xD;
               affect the study&#xD;
        </textblock>
      </criteria>
      <gender>All</gender>
      <minimum_age>55 Years</minimum_age>
      <maximum_age>N/A</maximum_age>
      <healthy_volunteers>No</healthy_volunteers>
    </eligibility>
    <overall_official>
      <last_name>Lutfu Hanoglu, Prof. DR. MD</last_name>
      <role>Principal Investigator</role>
      <affiliation>Medipol University</affiliation>
    </overall_official>
    <overall_contact>
      <last_name>Lutfu Hanoglu, Prof. DR. MD</last_name>
      <phone>+90 444 8 544</phone>
      <email>lhanoglu@kure.com.tr</email>
    </overall_contact>
    <overall_contact_backup>
      <last_name>Cennet Sena Parlatan, PhD Cand</last_name>
      <phone>05077799164</phone>
      <email>cennetsenaparlatan@gmail.com</email>
    </overall_contact_backup>
    <location>
      <facility>
        <name>Medipol University Hospital</name>
        <address>
          <city>Istanbul</city>
          <zip>34214</zip>
          <country>Turkey</country>
        </address>
      </facility>
      <status>Recruiting</status>
      <contact>
        <last_name>Lutfu Hanoglu, MD, PhD</last_name>
        <phone>0090 212 460 70 30</phone>
        <email>lhanoglu@kure.com.tr</email>
      </contact>
      <investigator>
        <last_name>Lutfu Hanoglu, MD, PhD</last_name>
        <role>Principal Investigator</role>
      </investigator>
    </location>
    <location_countries>
      <country>Turkey</country>
    </location_countries>
    <verification_date>July 2023</verification_date>
    <study_first_submitted>June 2, 2023</study_first_submitted>
    <study_first_submitted_qc>July 27, 2023</study_first_submitted_qc>
    <study_first_posted type="Actual">August 4, 2023</study_first_posted>
    <last_update_submitted>July 27, 2023</last_update_submitted>
    <last_update_submitted_qc>July 27, 2023</last_update_submitted_qc>
    <last_update_posted type="Actual">August 4, 2023</last_update_posted>
    <responsible_party>
      <responsible_party_type>Principal Investigator</responsible_party_type>
      <investigator_affiliation>Istanbul Medipol University Hospital</investigator_affiliation>
      <investigator_full_name>Prof. Lutfu Hanoglu, MD</investigator_full_name>
      <investigator_title>Prof Dr MD</investigator_title>
    </responsible_party>
    <keyword>Alzheimer's Disease</keyword>
    <keyword>TMS-EEG</keyword>
    <keyword>Machine learning</keyword>
    <keyword>Anti-inflammatory-neuroprotective-antioxidant effect</keyword>
    <condition_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Alzheimer Disease</mesh_term>
    </condition_browse>
    <patient_data>
      <sharing_ipd>No</sharing_ipd>
      <ipd_description>Data will not be shared due to ethical reasons</ipd_description>
    </patient_data>
    <!-- Results have not yet been posted for this study                                          -->
  </clinical_study>
  
  
text: download date: ClinicalTrials.gov processed this data on September 20, 2023
  link text: Link to the current ClinicalTrials.gov record.
  url: https://clinicaltrials.gov/ct2/show/NCT05977088
  org study id: 221S749
  nct id: NCT05977088
  lead sponsor: 
  collaborator: 
  collaborator: 
  has dmc: No
  is fda regulated drug: No
  is fda regulated device: No
  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. Another goal is to develop a personalized TMS treatment protocol based on the
        effect of Test Dose TMS on EEG and change in brain networks that can be viewed from EEG data
        generally before and after 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.
  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. Another goal is to develop a personalized TMS treatment protocol based on the
        effect of Test Dose TMS on EEG and change in brain networks that can be viewed from EEG data
        generally before and after 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. After then,
        Test Dose TMS of 150 beats at 20 Hz will be applied to left dorsolateral prefrontal cortex.
        Immediately after this Test Dose rTMS, the patient's resting state EEG data will be taken
        again. 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, the effect of Test Dose TMS on EEG will be investigated, the
        algorithm that predicts individuals who will benefit from TMS through pre-TMS EEG data and
        Test Dose TMS-EEG data will be investigated and The effect of TMS treatment on EEG will be
        investigated. Therefore, the prediction algorithm will open the door to personalized
        treatment protocol. 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.
  
        Within the scope of the project, a workshop, sharing of study results in
        national-international congresses, a patent application originating from algorithm
        production, production of 3 graduate students' thesis and at least 3 scientific articles will
        be produced. In addition, the investigators anticipate that TMS prevalence will increase
        during the treatment process of Alzheimer's patients, and the socio-economic burden caused by
        this disease will be reduced.
  allocation: Randomized
  intervention model: Parallel Assignment
  primary purpose: Diagnostic
  masking: Single (Participant)
  measure: The Mini Mental State Examination
  time frame: Changes Before Treatment and 1 month after treatment
  description: Cognitive Neuropsychological Test Score
  measure: Neuropsychiatric Inventory
  time frame: Changes Before Treatment and 1 month after treatment
  description: Cognitive Neuropsychological Test Score
  measure: Alzheimer's Disease Assessment Scale
  time frame: Changes Before Treatment and 1 month after treatment
  description: Cognitive Neuropsychological Test Score
  measure: ADSL
  time frame: Changes Before Treatment and 1 month after treatment
  description: Cognitive Neuropsychological Test Score
  measure: Geriatric Depression Scale
  time frame: Changes Before Treatment and 1 month after treatment
  description: Cognitive Neuropsychological Test Score
  measure: Blood samples ELISA analyses
  time frame: Changes Before Treatment and 1 month after treatment
  description: 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.
  measure: Blood samples analyses
  time frame: Changes Before Treatment and 1 month after treatment
  description: 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.
  measure: Inflammatory Biomarker analyses
  time frame: Changes Before Treatment and 1 month after treatment
  description: 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.
  measure: Oxidative Stress Biomarker analyses
  time frame: Changes Before Treatment and 1 month after treatment
  description: 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.
  measure: Evaluation of Fatty Acid Profile Analysis with GC-MS
  time frame: Changes Before Treatment and 1 month after treatment
  description: 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
  measure: Metabolomics Analysis by Liquid Chromatography-Mass Spectrometer/Mass Spectrometer (LC-MS/MS)
  time frame: Changes Before Treatment and 1 month after treatment
  description: 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
  measure: EEG Power Spectrum Analysis
  time frame: Changes Before Treatment and 1 month after treatment
  description: 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.
  measure: EEG Coherence Analysis
  time frame: Changes Before Treatment and 1 month after treatment
  description: 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.
  measure: EEG functional connectivity analysis
  time frame: Changes Before Treatment and 1 month after treatment
  description: eLORETA software will be used for functional connectivity analysis. sLORETA /eLORETA is an online free software developed by Roberto Pascual-Marqui and his team (http://www.uzh.ch/keyinst/loreta.htm). eLORETA is an algorithm developed to solve the inverse problem and it does not contain localization bias even in the presence of noise (Pascual-Marqui, 2007). In this software, resting state data with eyes closed, separated into 2 second epochs, whose artifacts are cleaned by preprocessing, will be used. The relevant areas to be analyzed in the cortical plane and the relevant frequency band gaps will be determined. The time series containing the eLORETA current source density obtained from these areas will be calculated and a "lagged linear coherence" matrix will be created to be applied in graph theory (Vecchio et al., 2014). "Lagged linear coherence" will give correct physiological connectivity unaffected by volume conduction and low spatial resolution (Pascual-Marqui et al., 2011).
  measure: EEG Analysis by Machine Learning
  time frame: Changes Before Treatment and 1 month after treatment
  description: The machine learning method was created based on the current experimental design and the planned number of patients. After the data is cleared and ready for analysis, the differences in the EEG signals of the patients who benefited from rTMS after the Test Dose TMS from the EEG signals after the Test Dose TMS of the patients who did not benefit will be revealed by a classification method. For this purpose, it is planned to implement the Support Vector Machines (SVM) method. The DVM method is the most suitable for our data and the project purpose among the machine learning methods with its high classification success in large-sized data that is difficult to parse.
  arm group label: Interventional
  arm group type: Experimental
  description: 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.
  Patients will be given two stimulations (pulse duration=3.5 sec, interval between beats=45 sec) consisting of only 75 beats, 100% of the cap threshold value compatible with the magnetic field TMS determined just before the rTMS routine application, and a total of 150 pulses of Test Dose TMS will be applied. A resting state EEG (eyes open-closed) will be taken immediately after (max. 2 minutes later) in the Faraday cage.
  arm group label: Sham
  arm group type: Sham Comparator
  description: The same treatment procedures will be applied to the control group with a sham coil.
  intervention type: Device
  intervention name: Repetetive Transcranial Magnetic Stimulation
  description: .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.
  Patients will be given two stimulations (pulse duration=3.5 sec, interval between beats=45 sec) consisting of only 75 beats, 100% of the cap threshold value compatible with the magnetic field TMS determined just before the rTMS routine application, and a total of 150 pulses of Test Dose TMS will be applied. A resting state EEG (eyes open-closed) will be taken immediately after (max. 2 minutes later) in the Faraday cage. The same procedures will be done with the sham coil in the control group.
  arm group label: Interventional
  arm group label: Sham
  other name: Electroensefolography
  criteria: 
  gender: All
  minimum age: 55 Years
  maximum age: N/A
  healthy volunteers: No
  last name: Lutfu Hanoglu, Prof. DR. MD
  role: Principal Investigator
  affiliation: Medipol University
  last name: Lutfu Hanoglu, Prof. DR. MD
  phone: +90 444 8 544
  email: lhanoglu@kure.com.tr
  last name: Cennet Sena Parlatan, PhD Cand
  phone: 05077799164
  email: cennetsenaparlatan@gmail.com
  facility: 
  status: Recruiting
  contact: 
  investigator: 
  country: Turkey
  responsible party type: Principal Investigator
  investigator affiliation: Istanbul Medipol University Hospital
  investigator full name: Prof. Lutfu Hanoglu, MD
  investigator title: Prof Dr MD
  mesh term: Alzheimer Disease
  sharing ipd: No
  ipd description: Data will not be shared due to ethical reasons