Ignite Creation Date:
2024-05-05 @ 4:59 PM
Last Modification Date:
2024-10-26 @ 9:26 AM
Study NCT ID:
NCT00362843
Status:
COMPLETED
Last Update Posted:
2024-06-13
First Post:
2006-08-09
Brief Title:
Protein Synthesis in the Brain of Patients With Fragile X Syndrome
Sponsor:
National Institute of Mental Health NIMH
Organization:
National Institutes of Health Clinical Center CC
Study Overview
Official Title:
PET Measurement of Regional Rates of Cerebral Protein Synthesis in Subjects With Fragile X Syndrome
Status:
COMPLETED
Status Verified Date:
2024-10
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief 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 14Cleucine 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 14Cleucine method it uses L 1 11Cleucine 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 11Cleucine PET method We propose three studies to be carried out sequentially In Part I we will establish the L-1-11Cleucine PET method in human subjects In Part II we will measure rCPS in normal control subjects in two states awake and under deep sedationgeneral 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 11Cleucine 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 eg in the investigation of disorders of brain development recovery from brain injury and neurodegenerative diseases
SPECIFIC AIMS
1 TABEstablish the L-1-11Cleucine PET method for measurement of rCPS in human subjects Evaluate the optimal scan time and the variability of the measurement in an individual
2 TABDetermine the effect of deep sedation with propofol on rCPS in normal human subjects We will use the 1-11Cleucine PET method to evaluate lambda ie 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
ITABHypothesis 1a Deep sedation with propofol has effects on rCPS
IITABHypothesis 1b Deep sedation with propofol has effects on values of lambda
3 TABAssess the sensitivity of the 1-11Cleucine PET method to detect differences in rCPS in subjects with fragile X syndrome
ITABHypothesis 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
IITABHypothesis 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
IIITABHypothesis 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
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 14Cleucine method it uses L 1 11Cleucine 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 11Cleucine PET method We propose three studies to be carried out sequentially In Part I we will establish the L-1-11Cleucine PET method in human subjects In Part II we will measure rCPS in normal control subjects in two states awake and under deep sedationgeneral 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 11Cleucine 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 eg in the investigation of disorders of brain development recovery from brain injury and neurodegenerative diseases
SPECIFIC AIMS
1 TABEstablish the L-1-11Cleucine PET method for measurement of rCPS in human subjects Evaluate the optimal scan time and the variability of the measurement in an individual
2 TABDetermine the effect of deep sedation with propofol on rCPS in normal human subjects We will use the 1-11Cleucine PET method to evaluate lambda ie 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
ITABHypothesis 1a Deep sedation with propofol has effects on rCPS
IITABHypothesis 1b Deep sedation with propofol has effects on values of lambda
3 TABAssess the sensitivity of the 1-11Cleucine PET method to detect differences in rCPS in subjects with fragile X syndrome
ITABHypothesis 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
IITABHypothesis 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
IIITABHypothesis 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-1-14Cleucine 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-1-14Cleucine method it uses L-1-11Cleucine 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-1-11Cleucine PET method Three studies will be carried out sequentially In Part I we have established the L-1-11Cleucine PET method in human subjects Three studies to be carried out sequentially In Part I we will establish the L-1-11Cleucine PET method in human subjects In Part II we measured rCPS in normal control subjects in two states awake and under deep sedationgeneral 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-1-11Cleucine 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 eg in the investigation of disorders of brain development recovery from brain injury and neurodegenerative diseases
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-1-14Cleucine method it uses L-1-11Cleucine 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-1-11Cleucine PET method Three studies will be carried out sequentially In Part I we have established the L-1-11Cleucine PET method in human subjects Three studies to be carried out sequentially In Part I we will establish the L-1-11Cleucine PET method in human subjects In Part II we measured rCPS in normal control subjects in two states awake and under deep sedationgeneral 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-1-11Cleucine 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 eg in the investigation of disorders of brain development recovery from brain injury and neurodegenerative diseases
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| 06-M-0214 | None | None | None |