Protein Synthesis in the Brain of Patients With Fragile X Syndrome
| Status: | Recruiting |
|---|---|
| Conditions: | Healthy Studies, Other Indications |
| Therapuetic Areas: | Other |
| Healthy: | No |
| Age Range: | 18 - 24 |
| Updated: | 12/20/2018 |
| Start Date: | August 8, 2006 |
| Contact: | Niharika Loomba |
| Phone: | (301) 451-8995 |
PET Measurement of Regional Rates of Cerebral Protein Synthesis in Subjects With Fragile X Syndrome
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.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.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)Hypothesis 1a. Deep sedation with propofol has effects on rCPS.
II)Hypothesis 1b. Deep sedation with propofol has effects on values of lambda.
3.Assess the sensitivity of the [1-(11)C]leucine PET method to detect differences in
rCPS in subjects with fragile X syndrome.
I)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)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)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.
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.
subjects. Evaluate the optimal scan time and the variability of the measurement in an
individual.
2.
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)
II)
3.
rCPS in subjects with fragile X syndrome.
I)
X syndrome compared with age-matched healthy controls. Regions affected include hippocampus,
thalamus, hypothalamus, amygdala, and frontal and parietal cortex.
II)
cortex rCPS are unchanged in subjects with fragile X syndrome compared with age-matched
healthy controls.
III)
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.
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. The
rationale was that 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 are studying
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.
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. The
rationale was that 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 are studying
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.
- 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 a high level of 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.
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.
We found this trial at
1
site
9000 Rockville Pike
Bethesda, Maryland 20892
Bethesda, Maryland 20892
Phone: 800-411-1222
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