Brain P-gp and Inflammation in People With Epilepsy
- The brain is protected by a barrier that keeps toxins in the blood from reaching the brain. However, this barrier can also keep useful medications from reaching the brain. P-glycoprotein (P-gp) is a brain protein that is part of the blood-brain barrier. The level of P-gp is higher in people with epilepsy than in people without epilepsy. These different levels of P-gp may explain why some people have seizures that do not respond well to medications. Researchers want to see if P-gp can affect the response to epilepsy medications.
- Epilepsy may also be associated with brain inflammation. Researchers also want to look at the part of the brain affected by epilepsy to see if inflammation is present.
- To see if P-gp can affect the response to epilepsy medications.
- To see if inflammation is present in the part of the brain affected by epilepsy.
- < TAB> Individuals between 18 and 60 years of age who have temporal lobe epilepsy. We plan to study some patients whose seizures are well controlled by drugs, and some whose seizures are not controlled.
- < TAB>
- Healthy volunteers between 18 and 60 years of age.
- This study requires four or five visits to the NIH Clinical Center over the course of a year. The visits will be outpatient visits and will last from 2 to 5 hours.
- Participants will be screened with a physical exam and medical history. Blood and urine samples will be collected.
- All participants will have two positron emission tomography (PET) scans. The scans will take place during different visits. Different drugs will be used in each scan. One drug will be used to temporarily block the effect of P-gp in the brain. The other drug will show areas of inflammation in the brain.
- Participants with epilepsy will have a third PET scan. This scan will also look at P-gp activity in the brain. However, it will not use the drug that blocks the effect of P-gp.
- All participants will also have one magnetic resonance imaging scan. This scan will help show brain function.
|Study Design:||Time Perspective: Prospective|
|Official Title:||Positron Emission Tomography Measurement of Neuroinflammation and P-glycoprotein in Localization-Related Epilepsy|
- A secondary goal is to determine if inhibiting P-gp with tariquidar results in increased concentrations of anti-epileptic medications into the CSF, as a surrogate marker for increased penetration of these medications into the central nervous sys...
|Study Start Date:||July 2012|
1) To investigate the relationship between permeability-glycoprotein (P-gp) function, neuroinflammation, and drug-resistance in participants with temporal lobe epilepsy (TLE). 2) To attempt to detect an increased level of inflammation in epileptic foci. 3) To assess theeffect of genetic polymorphisms of P-gp on brain uptake of [11C]dLop and of genetic polymorphisms of TSPO on brain uptake of [11C]PBR28.
25 participants with drug-resistant focal epilepsy; 25 participants with drug responsive focal epilepsy; and 25 healthy volunteers.
Screening of enrolled participants will include a medical history, physical exam, electrocardiogram (ECG), and blood and urine laboratory testing. Blood samples will also be used for genetic polymorphism study. Healthy volunteers will receive two brain positron emission tomography (PET) scans with [11C]dLop and [11C]PBR28. Epilepsy participants will receive three PET scans (2 with [11C]dLop and 1 with [11C]PBR28). Everyone will receive a brain magnetic resonance imaging (MRI). Because [11C]dLop uptake is influenced by blood flow, a [15O]H2O scan will also be performed to determine flow to the brain before each [11C]dLop scan. The [11C]dLop scan will be performed during infusion of intravenous tariquidar at up to 2 mg/kg, to partially block brain P-gp and ensure that some [11C]dLop enters the brain.
The primary outcome measure will be the amount of differential [11C]dLop and [11C]PBR28 uptake between the epileptic focus and the homologous contralateral region. [11C]dLop brain uptake will be measured in terms of standardized uptake values (SUV). SUV reflects the measured brain radioactivity after tracer injection, corrected for patient weight and injected activity. [11C]PBR28 distribution volume (VT) will be measured using an arterial input function. We want to quantify the tracer VT in regions of the brain distant from the epileptic focus, which may be affected by the disease. For this kind of quantification, the SUV is unsuitable, because it provides only a crude estimate of brain uptake, without taking into account the rate of delivery from the blood.
After P-gp blocking with tariquidar, we expect, in participants with drug-resistant epilepsy, that the amount of [11C]dLop uptake on the side of the epileptic focus will be lower than in the contralateral side. This difference will be significantly greater than the side-to side difference found in healthy participants. We expect an intermediate difference in the population of drug-responsive epilepsy participants. [11C]dLop uptake will be corrected for cerebral blood flow using [15O]H2 O PET.
We also hypothesize that TLE will be associated with brain inflammation and, therefore, that [11C]PBR28 uptake in the affected side of the brain will be higher than in the contralateral side. We will explore whether the degree of inflammation correlates with drug resistance and [11C]dLop uptake.
Finally, we will perform genetic testing to study the effect of polymorphisms of P-gp on brain uptake of [11C]dLop and with inhibition by tariquidar. The primary polymorphism (C3435T) of interest is the one that has been associated with drug resistance in epilepsy. We will also study the polymorphism of the translocator protein (TSPO), because TSPO polymorphism has an influence on [11C]PBR28 binding. This polymorphism is due to the non-conservative amino-acid substitution at position 147 from alanine to threonine (Ala147Thr) in the fifth transmembrane domain of the TSPO protein. If new genetic findings are published in the literature about epilepsy and its relationship with inflammation and efflux transporters, we may perform other types of genetic testing on the blood samples we have collected. Prospective approval from the IRB will be obtained for any genetic testing that has clinical implications for participants.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01663545
|Contact: Patricia M Reeves-Tyer, R. EEG T.||(301) firstname.lastname@example.org|
|Contact: William H Theodore, M.D.||(301) email@example.com|
|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 firstname.lastname@example.org|
|Principal Investigator:||William H Theodore, M.D.||National Institute of Neurological Disorders and Stroke (NINDS)|