Validation of Molecular Neuroimaging Biomarkers in Huntington's Disease in View of Therapeutic Trials Targeting the Krebs Cycle
试验速览
- 阶段
- 不适用
- 状态
- 已完成
- 入组人数
- 81
- 试验地点
- 1
- 主要终点
- Cerebral pH values.
研究概览
简要总结
There is no curative treatment available today in Huntington disease (HD) despite the identification of the mutated gene 20 years ago. Nonetheless, safe and promising therapeutic strategies targeting brain energy metabolism are now becoming available.
In view of the small effect sizes of any clinical parameter in HD, robust neuroimaging biomarkers reflecting brain energy metabolism are therefore urgently needed to better assess the potential of therapeutics targeting the mitochondria, and especially the Krebs cycle. Identifying such biomarkers at the presymptomatic phase in HD also provides a unique window for therapeutic intervention, which can be used as a proof-of-concept for the real challenge of tomorrow's medicine: the prevention of neurodegeneration HDeNERGY is an observational study consisting of the transfer of methods from preclinical to clinical studies and their application in HD. HDeNERGY aim at optimizing MRI/MRS methods to study the dynamics of brain energy metabolism. At the CENIR (Centre de neuro-imagerie et de recherche, Paris) the determination of creatine kinase rate will be first validated in healthy volunteers (n=20) and then applied to the selected cohort of early affected HD patients (n=20), presymptomatic individuals (n=20) and controls (n=20) together with the methods previously validated in HD patients (Mochel et al., 2012b) to determine the ratio of inorganic phosphate (Pi)/ phosphocreatine (PCr) during visual stimulation in presymptomatic individuals. The Chemical Exchange Saturation Transfer (CEST) method on the 3T clinical scanner of CENIR will be first validated in healthy volunteers (n=20) and then applied to the selected cohort of early affected HD patients (n=20), presymptomatic individuals (n=20) and controls (n=20).
The cerebral synthesis rate of creatine phosphate and of brain glutamate concentrations and pH values will be compared between controls, HD patients and HD presymptomatic individuals, and correlated with clinical parameters (age, BMI, UHDRS).
详细描述
Compelling evidence indicate a key role of energy defects in neurodegenerative diseases (NDs). These defects would constitute extremely informative functional biomarkers of disease states and progression. Such functional biomarkers could be used as readouts for therapeutic efficacy in clinical trials, especially for drugs targeting brain energy metabolism. Magnetic Resonance Imaging (MRI) and Magnetic Resonance Spectroscopy (MRS) are likely the most promising approaches to validate brain biomarkers linked to energy metabolism. However, existing methods allowing "static" measures of metabolites concentrations offer only a fragmented vision of brain energy metabolism in NDs. The validation of novel and "dynamic" methods is urgently needed. Our project addresses this challenge for Huntington disease (HD).
Our study is an observational study consisting of the transfer of methods from preclinical to clinical studies and their application in HD.
This study comprises two period:
- Period 1: transfer of 31P saturation transfer and CEST methods from preclinical to clinical MRS/MRI platforms and the validation of these methods in healthy individuals;
- Period 2: compare brain metabolic markers in early individuals affected by HD, presymptomatic individuals and controls, using 31P saturation transfer and CEST methods.
The primary objectives are:
研究设计
- 研究类型
- Observational
- 观察模型
- Other
- 时间视角
- Prospective
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- 未提供
排除标准
- 未提供
结局指标
主要结局
Cerebral pH values.
时间窗: 1 day
Comparison between controls, HD patients and HD presymptomatic individuals of pH values
Cerebral synthesis rate of creatine phosphate
时间窗: 1 day
Comparison between controls, HD patients and HD presymptomatic individuals of the cerebral synthesis rate of creatine phosphate
Cerebral brain glutamate concentrations
时间窗: 1 day
Comparison between controls, HD patients and HD presymptomatic individuals of brain glutamate concentrations
次要结局
- Correlations between the ratio of phosphocreatine concentration at different time point and age of participants(1 day)
- Correlations between pH values and BMI(1 day)
- Correlations between the ratio of phosphocreatine concentration at different time points and BMI of participants.(1 day)
- Correlations between creatine phosphate synthetic rate and UHDRS(1 day)
- Correlations between glutamate concentrations and UHDRS(1 day)
- Measure concentration of brain phosphocreatine (PCr) and glutamate using 31P MRS and gluCEST respectively in healthy volunteers(1 day)
- Data integration of rate of phosphocreatine (PCr) synthesis and gluatamate concentrations.(1 day)
- Correlations between glutamate concentrations and age(inclusion visit)
- Correlations between glutamate concentrations and BMI(inclusion visit)
- Correlations between pH values and age(1 day)
- Correlations between pH values and UHDRS(1 day)