Neurobiological Analyses Within the FORESEE III Study
试验速览
- 阶段
- 不适用
- 发起方
- 入组人数
- 50
- 试验地点
- 1
- 主要终点
- Change from baseline in DNA methylation patterns in plasma at 12 month of deep brain stimulation (DBS)
研究概览
简要总结
In this observational, non-invasive clinical study different neurobiological analyses will be performed in a group of patients with severe treatment resistant major depression participating in an efficacy study of deep brain stimulation of the superolateral branch of the medial forebrain bundle (slMFB) - FORESEE III.
详细描述
This study is a sub-project of the FORESEE III study (Controlled Randomized Clinical Trial to assess Efficacy of Deep Brain Stimulation (DBS) of the slMFB in Patients with Treatment Resistant Major Depression). The FORESEE III study itself is a randomized, sham-controlled, double blind (patient and observer blinded) clinical trial to assess the antidepressant effect of DBS compared to sham.
The aim of this sub-project is to analyze the time-course of biological correlates of treatment resistant major depression as well as neurobiological markers of treatment response to treatment with DBS in a well-characterized patient population during 12 month of DBS.
Specific neurobiological analyses include testing of
- epigenetic markers (DNA methylation in candidate genes of depression and epigenome-wide association studies, EWAS)
- markers of neuroinflammation (cytokines, neuropeptides and other immune factors)
- micro RNAs and transcriptome signatures
- markers of neurodegeneration (neurofilament light protein)
- metabolomic analyses and
- endocrinological parameters including glucose tolerance.
All markers will be tested in blood samples (and urine samples for metaboloic profiling) before neurosurgery as well as at several time points during DBS and sham condition intervals.
研究设计
- 研究类型
- Observational
- 观察模型
- Cohort
- 时间视角
- Prospective
入排标准
- 年龄范围
- 20 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •All enrolled subjects of the Controlled Randomized Clinical Trial to assess Efficacy of Deep Brain Stimulation (DBS) of the slMFB in Patients with Treatment Resistant Major Depression (FORESEE III) may participate in this study.
排除标准
- •Non-Caucasian (because of requirements for genetic/epigenetic analyses)
- •Somatic diseases like diabetes, cancer and severe liver- and kidney-diseases
- •Healthy Controls:
- •Inclusion Criteria:
- •All healthy volunteers without any clinically significant psychiatric or somatic symptoms are eligible.
- •Exclusion Criteria:
- •Any clinically significant psychiatric symptoms
- •Conditions like diabetes, cancer or severe liver- and kidney diseases
- •Drug or alcohol abuse
结局指标
主要结局
Change from baseline in DNA methylation patterns in plasma at 12 month of deep brain stimulation (DBS)
时间窗: At baseline (up to 10 weeks before surgical device implantation) and at 12 month of DBS (end of study both groups)
Epigenetic mechanisms such as DNA methylation crucially govern gene function and have been shown to be temporally dynamic and responsive to environmental stress. Epigenetic patterns in blood, saliva or other peripheral material have been suggested to partly reflect central epigenetic processes. DNA will by isolated and undergo bisulfite conversion. Using pyro- and direct sequencing, samples will be analyzed for DNA methylation in candidate genes of depression.
Change from baseline in DNA methylation patterns in plasma at 1 month of deep brain stimulation (DBS)
时间窗: At baseline (up to 10 weeks before surgical device implantation) and at 1 month of DBS (week 5 group A, week 21 group B)
Epigenetic mechanisms such as DNA methylation crucially govern gene function and have been shown to be temporally dynamic and responsive to environmental stress. Epigenetic patterns in blood, saliva or other peripheral material have been suggested to partly reflect central epigenetic processes. DNA will by isolated and undergo bisulfite conversion. Using pyro- and direct sequencing, samples will be analyzed for DNA methylation in candidate genes of depression.
Change from baseline in neuroinflammatory and neuropeptide patterns at 12 month of deep brain stimulation (DBS)
时间窗: At baseline (up to 10 weeks before surgical device implantation) and at 12 month of DBS (end of study both groups)
A new method of analysis (Proseek® Multiplex Inflammation, Olink Bioscience, Uppsala, Sweden) will be used to determine any change in patterns of relevant neuropeptides and inflammatory markers. This multiplex proximity extension assay (PEA) will simultaneously analyze 92 different proteins, including cytokines, neuropeptides and other immune factors.
Change from baseline in transcriptome profiles at 1 month of deep brain stimulation (DBS)
时间窗: At baseline (up to 10 weeks before surgical device implantation) and at 1 month of DBS (week 5 group A, week 21 group B)
A massive parallel next generation deep sequencing (NGS) technology will be used followed by bioinformatic network analysis to determine intraindividual changes in exosomal miR ( (miRs, 19-22 nt long non-coding RNAs) and transcriptome profiles.
Change from baseline in exosomal Micro-RNA (miR) expression levels and transcriptome profiles at 4 month of deep brain stimulation (DBS)
时间窗: At baseline (up to 10 weeks before surgical device implantation) and at 4 month of DBS (week 17 group A, week 33 group B)
A massive parallel next generation deep sequencing (NGS) technology will be used followed by bioinformatic network analysis to determine intraindividual changes in exosomal miR ( (miRs, 19-22 nt long non-coding RNAs) and transcriptome profiles.
Change from baseline in exosomal Micro-RNA (miR) expression levels and transcriptome profiles at 12 month of deep brain stimulation (DBS)
时间窗: At baseline (up to 10 weeks before surgical device implantation) and at 12 month of DBS (end of study both groups)
A massive parallel next generation deep sequencing (NGS) technology will be used followed by bioinformatic network analysis to determine intraindividual changes in exosomal miR ( (miRs, 19-22 nt long non-coding RNAs) and transcriptome profiles.
Change from baseline in plasma levels of Neurofilament light protein at 1 month of deep brain stimulation (DBS)
时间窗: At baseline (up to 10 weeks before surgical device implantation) and at 1 month of DBS (week 5 group A, week 21 group B)
Neurofilament light protein is part of the neuroaxonal cytoskeleton and can be released into plasma following neuroaxonal damage. In plasma it will be measured by single-molecule array (SiMoA) assays.
Change from baseline in neuroinflammatory and neuropeptide patterns at 1 month of deep brain stimulation (DBS)
时间窗: At baseline (up to 10 weeks before surgical device implantation) and at 1 month of DBS (week 5 group A, week 21 group B)
A new method of analysis (Proseek® Multiplex Inflammation, Olink Bioscience, Uppsala, Sweden) will be used to determine any change in patterns of relevant neuropeptides and inflammatory markers. This multiplex proximity extension assay (PEA) will simultaneously analyze 92 different proteins, including cytokines, neuropeptides and other immune factors.
Change from baseline in neuroinflammatory and neuropeptide patterns at 4 month of deep brain stimulation (DBS)
时间窗: At baseline (up to 10 weeks before surgical device implantation) and at 4 month of DBS (week 17 group A, week 33 group B)
A new method of analysis (Proseek® Multiplex Inflammation, Olink Bioscience, Uppsala, Sweden) will be used to determine any change in patterns of relevant neuropeptides and inflammatory markers. This multiplex proximity extension assay (PEA) will simultaneously analyze 92 different proteins, including cytokines, neuropeptides and other immune factors.
Change from baseline in plasma levels of Neurofilament light protein at 2 days before surgical device implantation
时间窗: At baseline (up to 10 to 7 weeks before surgical device implantation) and at 2 days before surgical device implantation
Neurofilament light protein is part of the neuroaxonal cytoskeleton and can be released into plasma following neuroaxonal damage. In plasma it will be measured by single-molecule array (SiMoA) assays.
Change from baseline in plasma levels of Neurofilament light protein at 4 month of deep brain stimulation (DBS)
时间窗: At baseline (up to 10 weeks before surgical device implantation) and at 4 month of DBS (week 17 group A, week 33 group B)
Neurofilament light protein is part of the neuroaxonal cytoskeleton and can be released into plasma following neuroaxonal damage. In plasma it will be measured by single-molecule array (SiMoA) assays.
Change from baseline in plasma levels of Neurofilament light protein at 12 month of deep brain stimulation (DBS)
时间窗: At baseline (up to 10 weeks before surgical device implantation) and at 12 month of DBS (end of study both groups)
Neurofilament light protein is part of the neuroaxonal cytoskeleton and can be released into plasma following neuroaxonal damage. In plasma it will be measured by single-molecule array (SiMoA) assays.
Change from baseline in DNA methylation patterns in plasma at 4 month of deep brain stimulation (DBS)
时间窗: At baseline (up to 10 weeks before surgical device implantation) and at 4 month of DBS (week 17 group A, week 33 group B)
Epigenetic mechanisms such as DNA methylation crucially govern gene function and have been shown to be temporally dynamic and responsive to environmental stress. Epigenetic patterns in blood, saliva or other peripheral material have been suggested to partly reflect central epigenetic processes. DNA will by isolated and undergo bisulfite conversion. Using pyro- and direct sequencing, samples will be analyzed for DNA methylation in candidate genes of depression.
Change from baseline in systemic metabolic parameters at week 41
时间窗: At baseline (up to 10 weeks before surgical device implantation) and at week 41 (both groups)
Different systemic metabolic parameters will be measured in blood.
Change from baseline in metabolite profiles in plasma and urine at 1 month of deep brain stimulation (DBS)
时间窗: At baseline (up to 10 weeks before surgical device implantation) and at 1 month of DBS (week 5 group A, week 21 group B)
Metabolite profiles of plasma and urine samples will be analysed by chromatographic separation techniques, different mass spectrometric ionization modes and mass analyzers in order to assess molecular changes in the metabolome. The metabolomic methodologies may include fingerprinting, nontargeted, and targeted approaches, metabolic profiling and metabolic flux analysis.
Change from baseline in insuline resistance at week 41
时间窗: At baseline (up to 10 weeks before surgical device implantation) and at week 41 (both groups)
An oral glucose tolerance test with blood measures of glucose, insulin and c-peptide at several time points during a period of 3 hours after oral intake of 75g glucose will be performed.
Non-invasive blood pressure (mmHG)
时间窗: At test stimulation of the slMFB during neurosurgery
Measured with ClearSight System, Edwards Lifesciences (allowing non-invasive and real-time continuous hemodynamic monitoring).
Cardiac stroke volume (ml)
时间窗: At test stimulation of the slMFB during neurosurgery
Measured with ClearSight System, Edwards Lifesciences (allowing non-invasive and real-time continuous hemodynamic monitoring).
Cardiac stroke volume variation (%)
时间窗: At teststimulation of the slMFB during neurosurgery
Measured with ClearSight System, Edwards Lifesciences (allowing non-invasive and real-time continuous hemodynamic monitoring)
Systemic vascular resistance (mmHg⋅min⋅mL-1)
时间窗: At test stimulation of the slMFB during neurosurgery
Measured with ClearSight System, Edwards Lifesciences (allowing non-invasive and real-time continuous hemodynamic monitoring).
Change from baseline in metabolite profiles in plasma and urine at 4 month of deep brain stimulation (DBS)
时间窗: At baseline (up to 10 weeks before surgical device implantation) and at 4 month of DBS (week 17 group A, week 33 group B)
Metabolite profiles of plasma and urine samples will be analysed by chromatographic separation techniques, different mass spectrometric ionization modes and mass analyzers in order to assess molecular changes in the metabolome. The metabolomic methodologies may include fingerprinting, nontargeted, and targeted approaches, metabolic profiling and metabolic flux analysis.
Change from baseline in metabolite profiles in plasma and urine at 12 month of deep brain stimulation (DBS)
时间窗: At baseline (up to 10 weeks before surgical device implantation) and at 12 month of DBS (end of study both groups)
Metabolite profiles of plasma and urine samples will be analysed by chromatographic separation techniques, different mass spectrometric ionization modes and mass analyzers in order to assess molecular changes in the metabolome. The metabolomic methodologies may include fingerprinting, nontargeted, and targeted approaches, metabolic profiling and metabolic flux analysis.
次要结局
未报告次要终点
研究者
Thomas E. Schlaepfer, Prof. Dr.
Professor Dr. Thomas E. Schläpfer
University Hospital Freiburg