Analysis of Inflammatory Predictors and Gene Expression in Patients With Mild Cognitive Impairment

Study Overview
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Brief Summary
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A randomized, double-blind, placebo-controlled clinical trial will be conducted, using data from participants who met the diagnostic criteria for mild cognitive impairment and who participated in a primary clinical trial that investigated the effectiveness of treatment with tDCS for patients with this pathology. The study in question seeks to investigate differences in inflammatory profile and gene expression in peripheral blood of patients with MCI responders and non-responders to treatment with tDCS, where it is intended to establish a profile of biomarkers that can predict disease progression. Primary study participants will be assessed previously for eligibility, then randomized to receive sham or active tDCS. Then, they will be invited to participate in the prediction analysis study to identify the inflammatory profile and gene expression. The participants' venous blood will be collected during the clinical examination on the first day of treatment, before the first session of tDCS, with a new collection after the last session, that is, at the baseline and the end point of our study.

Detailed Description
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Healthy aging is associated with several changes in cortical function and these physiological differences are often interpreted as successful adaptation when cognitive performance is maintained; however, cognitive ability is not always preserved in aging. Mild cognitive impairment (MCI) is a cognitive decline syndrome commonly referred to as an intermediate phase between the expected cognitive decline of aging and pathological cognitive decline linked to dementia and generally does not interfere with daily activities. Pharmacological interventions have shown little positive impact and fail to demonstrate realizable benefits in mitigating cognitive decline in individuals with MCI and in preventing progression to Alzheimer's disease (AD). With this, there is a growing interest in exploring the benefits of non-pharmacological interventions such as Transcranial Direct Current Stimulation (tDCS), which can be a treatment modality to address the electrophysiological onset, deficits of metabolic and functional neural activation observed in MCI. Although tDCS has been studied in different dementias, there are still few studies investigating its use for MCI, with a significant lack of research in this area. Another issue to be explored is changes in the levels of biomarkers in body fluids and in specific brain regions of these patients, as they may allow the detection of cognitive changes even before the appearance of MCI. Different proteomic and genetic markers can result in a more accurate prediction of who will develop AD dementia in the future. The study in question seeks to investigate differences in the inflammatory profile and gene expression in the peripheral blood of patients with MCI responders and non-responders to treatment with tDCS, where it is intended to establish a profile of biomarkers that can predict the progression of the disease. Data from participants who met the diagnostic criteria for MCI and who participated in a clinical trial that investigated the effectiveness of treatment with tDCS for patients with this pathology will be used. Thus, it is necessary to mention the importance of early identification of the incipient forms of cognitive deficits, for the development of effective treatments. Several randomized controlled trials are underway to try to provide clinical evidence for the development of biomarkers that should provide the clinician with new tools to identify and treat MCI.

Official Title
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Analysis of Inflammatory Predictors and Differences in Gene Expression in Patients With Cognitive Impairment Responders and Non-responders to Neurostimulation: Clinical Trial, Double-Blind, Randomized

Conditions
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Cognitive Decline

Intervention / Treatment
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* Device: Direct Current Transcranial Stimulation - tDCS
* Device: Sham Intervention


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Individuals diagnosed with CCL will be included Individuals of both sexes, aged 65 and over Individuals who do not have diagnosis of dementia Exclusion Criteria: Subjects with unstable medical conditions Patients with metallic implants and pacemakers Epileptic patients Individuals using drugs / alcohol Those who are under regular use of hypnotics and benzodiazepines up to two weeks before the start of the study Those who are using medication with cholinergic inhibitors for more than two months before this clinical trial

Ages Eligible for Study
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Minimum Age: 65 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: A randomized, double-blind, placebo-controlled clinical trial will be conducted with patients diagnosed with Mild Cognitive Impairment, submitted to Direct Current Transcranial Stimulation sessions in a primary clinical trial. Both studies are in accordance with the guidelines of the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) (Moher & Chan, 2014), which is considered a tool composed of minimal contents of a clinical trial protocol.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: active tDCS<br>tDCS active, for 30 minutes for 5 consecutive days, with an anode positioned in the left dorsolateral prefrontal cortex and cathode electrode placed over the right supraorbital area. The EEG International 10-20 system will be taken as a reference. The current intensity will be defined from computational modeling, using Nuclear Magnetic Resonance (MRI) to estimate and individualize a dose to be administered. | Device: Direct Current Transcranial Stimulation - tDCS<br>* Active intervention<br>|
| Sham Comparator: Sham tDCS<br>The electrodes will be positioned in the same way as in the intervention group. However, individuals in this group will receive a stimulation that will last only 20-30 seconds. Subsequently, the device is switched off, no longer emitting current. | Device: Sham Intervention<br>* Direct Current Transcranial Stimulation - Sham intervention<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cognitive Function | To assess the primary outcome, the Mini Mental State Examination (MMSE) or Mini-Mental State Examination (MMSE), developed in the United States and published in 1975, will be used, whose maximum score is 30 points and includes questions about memory, attention , orientation, language and visuospatial skills (Folstein, Folstein, & McHugh, 1975). We will adopt the 24-point score for the standard cut, following recommendations expressed in the literature (Anthony, Le Resche, Niaz, Von Korff, & Folstein, 1982; Folstein, Folstein, & McHugh, 1975). In order to avoid false positives and false negatives, we will perform the stratification by levels or years of schooling, as educational level is the main predictor of MMSE performance (Bertolucci, Brucki, Campacci, & Juliano, 1994). | Evaluations will be carried out in the pre-intervention (T0) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Inflammatory biomarkers | We will analyze three inflammatory cytokines Il-6, Il-10 and tumor necrosis factor (TNFα) from a blood sample to compare their levels between the group treated with active current, responders and non-responders to neurostimulation. | The assessment will be carried out at time T1 (baseline). | 
| Genetic Biomarkers | For the genotyping of Neuregulin and alpha-synuclein markers, researchers will follow the method developed by Chomczynski and Sacchi (1987). Total RNA from peripheral blood sample will be extracted using Trizol reagent (Invitrogen). The results will be used as a prediction of the response to neurostimulation. | The assessment will be carried out at time T1 (baseline) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Mild cognitive impairment, Direct Current Transcranial Stimulation, Inflammatory biomarkers, Gene expression