Protein Synthesis in the Brain of Patients With Fragile X Syndrome

This study is currently recruiting participants. (see Contacts and Locations)
Verified August 2014 by National Institutes of Health Clinical Center (CC)
Sponsor:
Information provided by:
National Institutes of Health Clinical Center (CC)
ClinicalTrials.gov Identifier:
NCT00362843
First received: August 9, 2006
Last updated: September 16, 2014
Last verified: August 2014
  Purpose

Biosynthesis of proteins is essential for growth and continued maintenance of the entire neuron including axons, dendrites, and synaptic terminals, and it is clearly one of the important biochemical processes underlying adaptive changes in the nervous system. Studies in experimental animals with the quantitative autoradiographic L [1 (14)C]leucine method have demonstrated a number of the physiological and pathological conditions in which changes in regional rates of cerebral protein synthesis (rCPS) occur.

We have recently developed the first fully quantitative method for determining rCPS with positron emission tomography (PET). The PET method was adapted from the autoradiographic L [1 (14)C]leucine method; it uses L [1 (11)C]leucine as the PET tracer, dynamic scanning, and a kinetic modeling approach for quantification. This method was validated in nonhuman primates by comparison of PET measurements with those based on established biochemical and autoradiographic techniques.

The objective of the present study is to examine the degree to which changes in rCPS in human subjects can be quantified with the L [1 (11)C]leucine PET method. We propose three studies to be carried out sequentially. In Part I we will establish the L-[1-(11)C]leucine PET method in human subjects. In Part II we will measure rCPS in normal control subjects in two states: awake and under deep sedation/general anesthesia with propofol. A difference in rCPS between these two states may indicate that we can detect activity-dependent protein synthesis with the PET method. In Part III we will study subjects with fragile X syndrome. This patient group was chosen since the affected gene in fragile X syndrome codes for a protein that is thought to be a negative regulator of message translation. Thus an effect on protein synthesis may be very close to the underlying genetic abnormality in fragile X syndrome. Regionally selective increases in rCPS have been found in studies in a mouse model of this disease.

The present study will establish the sensitivity of the L [1 (11)C]leucine PET method to detect changes in rCPS in human subjects. A quantitative and sensitive method to measure rCPS with PET will augment the tools available for investigating the brain and its regional adaptive responses. Ultimately the method may have widespread applications, not only for the study of normal development and plasticity but also in clinical medicine, e.g., in the investigation of disorders of brain development, recovery from brain injury, and neurodegenerative diseases.

SPECIFIC AIMS

  1. < TAB> Establish the L-[1-(11)C]leucine PET method for measurement of rCPS in human subjects. Evaluate the optimal scan time and the variability of the measurement in an individual.
  2. < TAB> Determine the effect of deep sedation with propofol on rCPS in normal human subjects. We will use the [1-(11)C]leucine PET method to evaluate lambda, i.e., the fraction of the precursor pool for protein synthesis that is derived from arterial plasma, and rCPS in the same subjects under awake and deep sedation conditions.

    I)< TAB> Hypothesis 1a. Deep sedation with propofol has effects on rCPS.

    II)< TAB> Hypothesis 1b. Deep sedation with propofol has effects on values of lambda.

  3. < TAB> Assess the sensitivity of the [1-(11)C]leucine PET method to detect differences in rCPS in subjects with fragile X syndrome.

I)< TAB> Hypothesis 3a. There are regionally selective changes in rCPS in subjects with fragile X syndrome compared with age-matched healthy controls. Regions affected include hippocampus, thalamus, hypothalamus, amygdala, and frontal and parietal cortex.

II)< TAB> Hypothesis 3b. In centrum semiovale, cerebellum, striatum and occipital and temporal cortex rCPS are unchanged in subjects with fragile X syndrome compared with age-matched healthy controls.

III)< TAB> Hypothesis 3c. Values of lambda in the brain as a whole and in the regions examined are unchanged in subjects with fragile X syndrome compared with age-matched healthy controls.

IV) Hypothesis 3d. The average rate of protein synthesis in the brain as a whole is unchanged in subjects with fragile X syndrome compared with age-matched healthy controls.


Condition
Fragile X Syndrome
Healthy Volunteers

Study Type: Observational
Study Design: Time Perspective: Cross-Sectional
Official Title: PET Measurement of Regional Rates of Cerebral Protein Synthesis in Subjects With Fragile X Syndrome

Resource links provided by NLM:


Further study details as provided by National Institutes of Health Clinical Center (CC):

Primary Outcome Measures:
  • Regional rates of cerebral protein synthesis

Estimated Enrollment: 112
Study Start Date: August 2006
Detailed Description:

Biosynthesis of proteins is essential for growth and continued maintenance of the entire neuron including axons, dendrites, and synaptic terminals, and it is clearly one of the important biochemical processes underlying adaptive changes in the nervous system. Studies in experimental animals with the quantitative autoradiographic L-[1-(14)C]leucine method have demonstrated a number of the physiological and pathological conditions in which changes in regional rates of cerebral protein synthesis (rCPS) occur.

We have recently developed the first fully quantitative method for determining rCPS with positron emission tomography (PET). The PET method was adapted from the autoradiographic L-[1-(14)C]leucine method; it uses L-[1-(11)C]leucine as the PET tracer, dynamic scanning, and a kinetic modeling approach for quantification. This method was validated in nonhuman primates by comparison of PET measurements with those based on established biochemical and autoradiographic techniques.

The objective of the present study is to examine the degree to which changes in rCPS in human subjects can be quantified with the L-[1-(11)C]leucine PET method. We propose three studies to be carried out sequentially. In Part I we will establish the L-[1-(11)C]leucine PET method in human subjects. In Part II we will measure rCPS in normal control subjects in two states: awake and under deep sedation/general anesthesia with propofol. A difference in rCPS between these two states may indicate that we can detect activity-dependent protein synthesis with the PET method. In Part III we will study subjects with fragile X syndrome. This patient group was chosen since the affected gene in fragile X syndrome codes for a protein that is thought to be a negative regulator of message translation. Thus an effect on protein synthesis may be very close to the underlying genetic abnormality in fragile X syndrome. Regionally selective increases in rCPS have been found in studies in a mouse model of this disease.

The present study will establish the sensitivity of the L-[1-(11)C]leucine PET method to detect changes in rCPS in human subjects. A quantitative and sensitive method to measure rCPS with PET will augment the tools available for investigating the brain and its regional adaptive responses. Ultimately the method may have widespread applications, not only for the study of normal development and plasticity but also in clinical medicine, e.g., in the investigation of disorders of brain development, recovery from brain injury, and neurodegenerative diseases.

  Eligibility

Ages Eligible for Study:   18 Years to 24 Years
Genders Eligible for Study:   Male
Accepts Healthy Volunteers:   Yes
Criteria
  • INCLUSION CRITERIA:

Fragile X subjects:

Male subjects, 18-24 years of age, with diagnosis of fragile X syndrome will be considered. Diagnosis will be confirmed by molecular genetic testing. Subjects with CGG repeat sequences greater than 200 and methylation of FMR1 will be included.

Control:

Male subjects, 18-24 years of age will be considered.

EXCLUSION CRITERIA:

Fragile X subjects:

Fragile X subjects with either repeat size or methylation mosaicism will be excluded. Fragile X subjects on psychotropic medications will be excluded from the study. Fragile X subjects who have received radiation doses for research purposes exceeding 4 rem (whole body effective dose) in the previous 12 months will be excluded. Fragile X subjects in whom MRI is contraindicated will be excluded. Subjects with metal objects in their bodies, such as pacemakers, aneurysm clips (metal clips on the wall of a large artery), metallic prostheses, cochlear implants, or shrapnel fragments will be excluded from the study. Welders and metal workers at risk for eye injury because of unsuspected tiny metal fragments there will also be excluded. Subjects in whom sedation is contraindicated will be excluded. Fragile X subjects on medications that interfere with blood coagulation will be excluded (see Appendix 1). In addition, fragile X subjects with respiratory illnesses or cardiovascular diseases will be excluded as there might be increased risk of complications with sedation/anesthesia. Subjects positive for HIV will be excluded from the study.

Control:

Subjects with premutation alleles, i.e., repeat length between 55 and 200 will be excluded. Subjects with IQ less than 90 or subnormal language skills will be excluded. Subjects on psychotropic medication will be excluded from the study. Subjects who have received radiation doses for research purposes exceeding 3.5 rem (whole body effective dose) in the previous 12 months and subjects for whom MRI is contraindicated will be excluded. Subjects in whom sedation is contraindicated will be excluded from Part II. Subjects on medications that interfere with blood coagulation will be excluded (see Appendix 1). Subjects with any previous history of psychiatric or neurological disease, as assessed by the Structured Clinical Interview for DSM-IV (SCID), will be excluded. In addition, subjects with respiratory illnesses or cardiovascular diseases will be excluded from Part II as there might be increased risk of complications with sedation/anesthesia. Subjects positive for HIV will be excluded from the study. Subjects with positive results on the urine drug screen will be excluded.

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00362843

Contacts
Contact: Brittney C Evans (301) 451-8995 brittney.evans@nih.gov
Contact: Carolyn B Smith, Ph.D. (301) 451-8995 beebe@mail.nih.gov

Locations
United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact Patient Recruitment and Public Liaison Office (PRPL)    800-411-1222 ext TTY8664111010    prpl@mail.cc.nih.gov   
Sponsors and Collaborators
Investigators
Principal Investigator: Carolyn B Smith, Ph.D. National Institute of Mental Health (NIMH)
  More Information

Additional Information:
Publications:
ClinicalTrials.gov Identifier: NCT00362843     History of Changes
Other Study ID Numbers: 060214, 06-M-0214
Study First Received: August 9, 2006
Last Updated: September 16, 2014
Health Authority: United States: Federal Government

Keywords provided by National Institutes of Health Clinical Center (CC):
11C-Leucine
Positron Emission Tomography (PET)
Cerebral Protein Synthesis
Propofol
Fragile X
Fragile X Syndrome

Additional relevant MeSH terms:
Fragile X Syndrome
Syndrome
Disease
Pathologic Processes
Mental Retardation, X-Linked
Intellectual Disability
Neurobehavioral Manifestations
Neurologic Manifestations
Nervous System Diseases
Sex Chromosome Disorders
Chromosome Disorders
Congenital Abnormalities
Genetic Diseases, Inborn
Genetic Diseases, X-Linked
Heredodegenerative Disorders, Nervous System

ClinicalTrials.gov processed this record on October 01, 2014