Protein Synthesis in the Brain of Patients With Fragile X Syndrome

2015-04-09 04:50:48 | BioPortfolio

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.

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.

Study Design

Time Perspective: Cross-Sectional

Conditions

Fragile X Syndrome

Location

National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda
Maryland
United States
20892

Status

Recruiting

Source

National Institutes of Health Clinical Center (CC)

Results (where available)

View Results

Links

Published on BioPortfolio: 2015-04-09T04:50:48-0400

Clinical Trials [485 Associated Clinical Trials listed on BioPortfolio]

Trial of Minocycline to Treat Children With Fragile X Syndrome

This is a single center study at the UC Davis MIND Institute in patients age 3.5-16 years of age with fragile X syndrome (FXS), funded by a National Fragile X Foundation Grant. It is a con...

A Safety Study of NNZ-2566 in Patients With Fragile X Syndrome

The purpose of this study is to determine whether NNZ-2566 is safe and well tolerated in the treatment of Fragile X Syndrome in adolescent and adult males.

A Study With RO4917523 in Patients With Fragile X Syndrome

This randomized, double-blind multiple ascending dose study will evaluate the safety and tolerability, pharmacokinetics and efficacy of RO4917523 in patients with Fragile X Syndrome. The p...

Riluzole in Fragile X Syndrome

The purpose of this study is to investigate the effectiveness and tolerability of riluzole in adults with Fragile X Syndrome.

A Study of RO4917523 in Pediatric Patients With Fragile X Syndrome

This randomized, double-blind, placebo-controlled, parallel-arm study will evaluate the safety and exploratory efficacy and pharmacokinetics of RO4917523 in pediatric patients with fragile...

PubMed Articles [5020 Associated PubMed Articles listed on BioPortfolio]

Positron Emission Tomography (PET) Quantification of GABAA Receptors in the Brain of Fragile X Patients.

Over the last several years, evidence has accumulated that the GABAA receptor is compromised in animal models for fragile X syndrome (FXS), a common hereditary form of intellectual disability. In mous...

Dysregulated Dscam levels act through Abelson tyrosine kinase to enlarge presynaptic arbors.

Increased expression of Down Syndrome Cell Adhesion Molecule (Dscam) is implicated in the pathogenesis of brain disorders such as Down syndrome (DS) and fragile X syndrome (FXS). Here, we show that th...

Detection of skewed X-chromosome inactivation in Fragile X syndrome and X chromosome aneuploidy using quantitative melt analysis.

Methylation of the fragile X mental retardation 1 (FMR1) exon 1/intron 1 boundary positioned fragile X related epigenetic element 2 (FREE2), reveals skewed X-chromosome inactivation (XCI) in fragile X...

Increased coupling of caveolin-1 and ERα contributes to the Fragile X syndrome.

Objective: Fragile X syndrome (FXS) is a form of inherited mental retardation in humans that results from expansion of a CGG repeat in the Fmr1 gene. Interaction between estrogen receptor (ER) and lip...

Psychiatric and Social Aspects of Patients with Fragile X Syndrome.

Objective: The goal of the study was to describe the burden of psychosocial risks, of mental illnesses and the ways of treatment of patients with fragile X syndrome (FRX). Method: Data from a sample o...

Medical and Biotech [MESH] Definitions

Specific loci that show up during KARYOTYPING as a gap (an uncondensed stretch in closer views) on a CHROMATID arm after culturing cells under specific conditions. These sites are associated with an increase in CHROMOSOME FRAGILITY. They are classified as common or rare, and by the specific culture conditions under which they develop. Fragile site loci are named by the letters "FRA" followed by a designation for the specific chromosome, and a letter which refers to which fragile site of that chromosome (e.g. FRAXA refers to fragile site A on the X chromosome. It is a rare, folic acid-sensitive fragile site associated with FRAGILE X SYNDROME.)

A RNA-binding protein that is found predominately in the CYTOPLASM. It helps regulate GENETIC TRANSLATION in NEURONS and is absent or under-expressed in FRAGILE X SYNDROME.

An increased number of contiguous trinucleotide repeats in the DNA sequence from one generation to the next. The presence of these regions is associated with diseases such as FRAGILE X SYNDROME and MYOTONIC DYSTROPHY. Some CHROMOSOME FRAGILE SITES are composed of sequences where trinucleotide repeat expansion occurs.

A condition characterized genotypically by mutation of the distal end of the long arm of the X chromosome (at gene loci FRAXA or FRAXE) and phenotypically by cognitive impairment, hyperactivity, SEIZURES, language delay, and enlargement of the ears, head, and testes. MENTAL RETARDATION occurs in nearly all males and roughly 50% of females with the full mutation of FRAXA. (From Menkes, Textbook of Child Neurology, 5th ed, p226)

Condition with a variable constellation of phenotypes due to deletion polymorphisms at chromosome location 22q11. It encompasses several syndromes with overlapping abnormalities including the DIGEORGE SYNDROME, VELOCARDIOFACIAL SYNDROME, and CONOTRUNCAL AMOMALY FACE SYNDROME. In addition, variable developmental problems and schizoid features are also associated with this syndrome. (From BMC Med Genet. 2009 Feb 25;10:16) Not all deletions at 22q11 result in the 22q11deletion syndrome.

More From BioPortfolio on "Protein Synthesis in the Brain of Patients With Fragile X Syndrome"


Advertisement
 
Advertisement
 

Searches Linking to this Trial