PET-MRI F-DOPA Activity in the Mesocorticolimbic System and Depressive Symptoms in the Prediction of Treatment Compatibility
试验速览
- 阶段
- 不适用
- 入组人数
- 60
- 主要终点
- 3,4-dihydroxy-6-[18F]-fluoro-l-phenylalanine ([18F] FDOPA) uptake rate constant (K(i)) that reflects L-dopa transport.
研究概览
简要总结
Main objectives: Comparing levels of F-DOPA reuptake rate as an indicator for Dopamine metabolism of un-medicated Depressed patients to healthy individuals in the Mesocorticolimbic System (VTA-NAc-PFC) and assessing structural differences between the two groups in the Hippocampus, Hypothalamic-Pituitary gland and Mesocorticolimbic System (VTA-NAc-PFC) and resting state fMRI.
Secondary objectives: 1. Comparing the differences of DNA Methylation in the plasma and serum of patients compared to healthy controls. 2.Assessing the correlation between symptoms' severity score (evaluated based on Hamilton Rating Scale) at base line and 6 months following treatmnt to PET 18F-DOPA uptake repertoire in the Mesocorticolimbic System, structural measurements and DNA Methylation.
Methodology: Study Design: A prospective, pilot study. 30 un medicated Depressed patients and 30 Healthy volunteers will perform a [18F] FDOPA PET/MRI scans following a HAM-D questionnaire (Hamilton rating scale of depression) and blood tests.
PET-MR (Biograph mMR, Siemens AG, Erlangen, Germany) scans will be performed using the tracer of dopamine precursor 3,4-dihydroxy-6-[18F]-fluoro-l-phenylalanine ([18F] FDOPA) that reflects L-dopa transport, L-aromatic amino acid decarboxylase activity, vesicular uptake and the number of dopamine nerve terminals. Measurements of dynamic F-DOPA parameters (Ki) and quantitative measurements of static F-DOPA ( SUVmax and SUVmean) will be performed in the ventral tagmental area (VTA), nucleus accombens (NAc) and pre-frontal cortex (PFC)which comprise the Mesocorticolimbic System, bilaterally. MRI sequences of T1, T2 3D measurements (assessing Volume) of the hippocampus, Hypothalamic-Pituitary gland and Mesocorticolimbic system, DTI measurements in the mesocorticolimbic dopaminergic tract and BOLD (resting-state f-MRI) in those brain networks. whole genome DNA Methylation from whole blood will be performed.
To date there is no quantative standard of care evaluation tool that serves psychiatrists when assigning medication for newly diagnosed depressed patients. The manner in which medications are assigned are threw symptom evaluation and trial and error. Only a third of the patients achieve remission after the first line of treatment. SSRI's are most common type of medication used to treat Major Depression today. One third of patients remains un responsive even after the fourth line of treatment (of different types of medications). Anti depression medications way of action requires time to reach its effect and in many patients with no avail or even causing symptom's severity. The PET-MR multimodality imaging tool offers a cutting edge technology ideally fitted to measure brain disorders. The use of F-DOPA radio-ligand with the PET-MR constitutes a novelty in the imaging of the depressed brain. Dopamine is one of three of the monoamine neurotransmitters targeted by anti-depressive medication, sharing metabolistic agents. dopamine has been proven to be connected to the processing of emotion, motivation, hedonism and reward threw its action in the Meso-cortico-limbic system. Epigenetics is a regulatory system that determines gene expression. It is heritable in the one hand and reacts to environmental changes on the other. It has been shown to be involved in psychiatric disorders.
PET-MR scans will be performed. DNA samples will be extracted from subject's whole blood samples taken prior to scans. Then it will be analyzed for whole genome DNA methylation. Taken together this novelty imaging technique and epigenetic mapping of peripheral markers can be used to better understand and personalize anti-depressive treatment compatibility.
详细描述
Introduction:
Major depressive disorder (MDD) is a versatile psychiatric disorder with a prevalence of 8-12 % of the population in many countries.
According to current approach MDD is characterized by lowered activity of monoamine neurotransmitters, it is undetermined whether it is as a result of differences in sensitivity of their receptors or depletion in the synaptic cleft due to low expression or mao-a/mao-b hyperactivity.
Most antidepressant medication used today are based on the monoamine depletion theory of depression. These medications include selective serotonine reuptake inhibitors (SSRIs), serotonine norepinephrine reuptake inhibitors (SNRI's) or Tricyclics anti-depressants (TCAs), all of which inhibit the reuptake of some or all of these monoamines, inducing elevated levels in the synaptic cleft. Some medications affect the monoamines receptors directly.
Dysfunctional dopamine neurotransmission has an essential role in deficits with attention, motivation and anhedonia which are core symptoms of depressive disorder. Pre-synaptic D2r (Dopamine 2 receptor) density in the pre frontal cortex (PFC) has shown to be significantly lower in depressed patients versus healthy individuals.
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
- 30 Years 至 50 Years（Adult）
- 性别
- Male
- 接受健康志愿者
- 是
入选标准
- 未提供
排除标准
- •With no history of psychiatric diagnosis.
- •History of any neurodegenerative disease or active oncologic disease.
- •With no history of psychiatric medication intake.
- •Patients treated with levodopa or any other medication known to interfere with the DAT or catechol O-methyltransferase inhibitors, or with dopamine receptor blocking / or catecholamine re-uptake blocking properties.
- •Contraindication to MR imaging.
- •study group- 30 Newly diagnosed depressed patient from the clinic of Dr. Lurie an extension of Shalvata Mental health center .
- •Inclusion criteria:
- •Adult male patients between the age of 30-50 years old.
- •Patients willing to participate with all the study procedures and sign informed consent form.
- •A clinical diagnosis of major depression.
- •With no history of psychiatric medication intake.
- •Scheduled to be treated with SSRI.
- •Exclusion criteria:
- •Psychiatric patients diagnosed and treated with any psychiatric medication.
- •History of any neurodegenerative disease or active oncologic disease.
- •Patients with history of other brain disorder/pathology.
- •Patients treated with levodopa or any other medication known to interfere with the DAT or catechol O-methyltransferase inhibitors, or with dopamine receptor blocking / or catecholamine re-uptake blocking properties.
- •Contraindication to MR imaging.
- •With suicidal symptoms.
- •Subject withdrawal criteria:
- •Subject who withdrawn his consent at any point of the study.
- •Inability to perform MR
- •Non compliant with treatment intake or follow up observations.
- •Any decision made by the investigator that termination is in subject's best intrest.
- •Serius adverse event relating to the study.
结局指标
主要结局
3,4-dihydroxy-6-[18F]-fluoro-l-phenylalanine ([18F] FDOPA) uptake rate constant (K(i)) that reflects L-dopa transport.
时间窗: at base line
次要结局
未报告次要终点
研究者
david groshar
david groshar
Assuta Medical Center