Dynamic Neuroimaging Biomarkers in Huntington's Disease (HDeNERGY)

Validation of Molecular Neuroimaging Biomarkers in Huntington's Disease in View of Therapeutic Trials Targeting the Krebs Cycle

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).

Study Overview

• Status: Completed
• Conditions: Brain Neuroimaging Biomarkers in Huntington Disease

Detailed Description

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:

Using 31P saturation transfer and CEST methods, the primary objective is to compare novel metabolic biomarkers between controls and HD carriers (patients and presymptomatic individuals).

Assessment criterion:

Comparison between controls, HD patients and HD presymptomatic individuals of the cerebral synthesis rate of creatine phosphate and of brain glutamate concentrations and pH values

The secondary objectives are:

• To develop/optimize 31P MRS/CEST methods to study the dynamics of brain energy metabolism in humans
• To improve the understanding and "modeling" the nature of energy deficits in HD
• To look for correlations between brain energy profiles and clinical scores.

Assessment criteria:

• Validation of the 31P MRS and CEST methods in healthy volunteers.
• Combination and integration of the 31P MRS and CEST data in order to obtain a model of energy deficits in HD.
• Correlations between creatine phosphate synthetic rate and clinical parameters (age, BMI, UHDRS); correlations between glutamate concentrations and clinical parameters; correlations between pH values and clinical parameters.

Ancillary studies:

The investigators wish to compare brain energy parameters (creatine phosphate synthetic rate, glutamate concentrations, pH values) with systemic metabolic markers (profiles of plasma metabolites obtained from metabolomic and lipidomic studies).

• Study Type: Observational
• Enrollment (Actual): 81

Contacts and Locations

Study Locations

• France
  • Paris, France
    • APHP - Pitié Salpetriere Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Period 1: healthy volunteers; Period 2: presymptomatic individuals, early affected HD patients and controls

Description

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

Study Plan

How is the study designed?

Design Details

• Observational Models: Other
• Time Perspectives: Prospective

Number of groups / cohorts

4

Cohorts and Interventions

Group / Cohort
healthy volunteers; 31P-MR Spectroscopy and CEST for Validation of MRI/MRS methods
HD presymptomatic individuals; General medical exam Clinical assessment with illness rating scales: Unified Huntington's Disease Rating Scale Total Motor Score (UHDRS) and Total Functional Capacity (TFC), 31P-MR Spectroscopy and CEST
early affected HD patients; General medical exam Clinical assessment with illness rating scales: UHDRS and TFC, 31P-MR Spectroscopy and CEST
Controls; General medical exam Clinical assessment with illness rating scales: UHDRS and TFC, 31P-MR Spectroscopy and CEST

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
Cerebral brain glutamate concentrations	Comparison between controls, HD patients and HD presymptomatic individuals of brain glutamate concentrations	1 day
Cerebral pH values.	Comparison between controls, HD patients and HD presymptomatic individuals of pH values	1 day

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
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
Correlations between the ratio of phosphocreatine concentration at different time point and age of participants		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 age		inclusion visit
Correlations between glutamate concentrations and BMI		inclusion visit
Correlations between glutamate concentrations and UHDRS		1 day
Correlations between pH values and age		1 day
Correlations between pH values and BMI		1 day
Correlations between pH values and UHDRS		1 day

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Collaborators: CEA
• Investigators: Principal Investigator: Fanny MOCHEL, MD, Assistance Publique - Hôpitaux de Paris

Study record dates

Study Major Dates

• Study Start (Actual): June 28, 2016
• Primary Completion (Actual): June 24, 2019
• Study Completion (Actual): June 24, 2019

Study Registration Dates

• First Submitted: December 15, 2015
• First Submitted That Met QC Criteria: December 21, 2015
• First Posted (Estimate): December 28, 2015

Study Record Updates

• Last Update Posted (Actual): August 8, 2019
• Last Update Submitted That Met QC Criteria: August 6, 2019
• Last Verified: August 1, 2019

More Information

Terms related to this study

• Keywords: Huntington disease; Neuroimaging metabolic biomarker
• Additional Relevant MeSH Terms: Mental Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurocognitive Disorders; Genetic Diseases, Inborn; Basal Ganglia Diseases; Movement Disorders; Neurodegenerative Diseases; Dyskinesias; Heredodegenerative Disorders, Nervous System; Dementia; Cognition Disorders; Chorea; Huntington Disease
• Other Study ID Numbers: P140708; 2015-A00793-46 (Other Identifier: IDCRB)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No