Brain Neuroimaging Biomarkers in Huntington Disease Clinical Trial
— HDeNERGYOfficial title:
Validation of Molecular Neuroimaging Biomarkers in Huntington's Disease in View of Therapeutic Trials Targeting the Krebs Cycle
| Verified date | August 2019 |
| Source | Assistance Publique - Hôpitaux de Paris |
| Contact | n/a |
| Is FDA regulated | No |
| Health authority | |
| Study type | Observational |
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).
| Status | Completed |
| Enrollment | 81 |
| Est. completion date | June 24, 2019 |
| Est. primary completion date | June 24, 2019 |
| Accepts healthy volunteers | Accepts Healthy Volunteers |
| Gender | All |
| Age group | 18 Years and older |
| Eligibility |
Inclusion criteria Healthy Volunteers Period 1: - At least 18 years of age - Signature of the informed consent - Covered by social security Participants Period 2: - At least 18 years of age - Signature of the informed consent - Covered by social security - Presymptomatic individuals: Positive genetic test with CAG repeat length > 39 in HTT gene, UHDRS score < 5 - Early affected patients: Positive genetic test with CAG repeat length > 39 in HTT gene and UHDRS score between 5 and 40 - BMI between 18 and 30 Non-inclusion criteria Healthy Volunteers Period 1: - Contra-indications to MRI (claustrophobia, metallic or material implants) - History of severe head injury - Participation in another trial - Pregnancy and breastfeeding - Inability to understand information about the protocol - Persons deprived of their liberty by judicial or administrative decision - Adult subject under legal protection or unable to consent. - Unwillingness to be informed in case of abnormal MRI Participants Period 2: - Contra-indications to MRI (claustrophobia, metallic or material implants) - Additional psychiatric or neurological conditions / Additional major comorbidities - History of severe head injury - Participation in another trial - Pregnancy and breastfeeding - Inability to understand information about the protocol - Persons deprived of their liberty by judicial or administrative decision - Adult subject under legal protection or unable to consent. - Unwillingness to be informed in case of abnormal MRI - Treatment with tetrabenazine |
| Country | Name | City | State |
|---|---|---|---|
| France | APHP - Pitié Salpetriere Hospital | Paris |
| Lead Sponsor | Collaborator |
|---|---|
| Assistance Publique - Hôpitaux de Paris | CEA |
France,
| Type | Measure | Description | Time frame | Safety issue |
|---|---|---|---|---|
| Primary | Cerebral synthesis rate of creatine phosphate | Comparison between controls, HD patients and HD presymptomatic individuals of the cerebral synthesis rate of creatine phosphate | 1 day | |
| Primary | Cerebral brain glutamate concentrations | Comparison between controls, HD patients and HD presymptomatic individuals of brain glutamate concentrations | 1 day | |
| Primary | Cerebral pH values. | Comparison between controls, HD patients and HD presymptomatic individuals of pH values | 1 day | |
| Secondary | Measure concentration of brain phosphocreatine (PCr) and glutamate using 31P MRS and gluCEST respectively in healthy volunteers | The 31P MRS will allow to measure the synthesis rate of PCr at different time points - rest, visual stimulation and recovery after stimulation. The rate of PCr synthesis will give an indication on the integrity of the rate of creatine-kinase. gluCEST will allow to measure the regional distribution of glutamate in the brain in order to create glutamate maps. |
1 day | |
| Secondary | Data integration of rate of phosphocreatine (PCr) synthesis and gluatamate concentrations. | A model of energy deficit in HD can be created by looking at the correlation between the rate of PCr synthesis, glutamate maps and the disease. | 1 day | |
| Secondary | Correlations between the ratio of phosphocreatine concentration at different time point and age of participants | 1 day | ||
| Secondary | Correlations between the ratio of phosphocreatine concentration at different time points and BMI of participants. | 1 day | ||
| Secondary | Correlations between creatine phosphate synthetic rate and UHDRS | 1 day | ||
| Secondary | Correlations between glutamate concentrations and age | inclusion visit | ||
| Secondary | Correlations between glutamate concentrations and BMI | inclusion visit | ||
| Secondary | Correlations between glutamate concentrations and UHDRS | 1 day | ||
| Secondary | Correlations between pH values and age | 1 day | ||
| Secondary | Correlations between pH values and BMI | 1 day | ||
| Secondary | Correlations between pH values and UHDRS | 1 day |