Protein Synthesis in the Brain of Patients With Fragile X Syndrome
Condition: Fragile X Syndrome; Healthy Volunteers
MeSH terms: Fragile X Syndrome; Syndrome
Study type: Observational

Summary: 
      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.
    

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. Three studies will be
      carried out sequentially. In Part I we have established the L-[1-11C]leucine PET method in
      human subjects. 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 measured rCPS in normal
      control subjects in two states: awake and under deep sedation/general anesthesia. 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 establishes 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.
    

Intervention name(s): [15-O]water
Intervention type(s): Drug
Observational model: Cohort
Time perspective: Cross-Sectional
Sampling method: Non-Probability Sample
Study population: 
        All of our subjects are adult, male volunteers between the ages of 18 and 24, either
        healthy volunteers or patients with Fragile X Syndrome.
      
Keywords: 11C-Leucine; Positron Emission Tomography (PET); Cerebral Protein Synthesis; dexmedetomidine; Brain Mapping; Natural History; Fragile X Syndrome