P-glycoprotein Function in Brain Diseases

This study has been completed.
Sponsor:
Information provided by:
National Institutes of Health Clinical Center (CC)
ClinicalTrials.gov Identifier:
NCT00677885
First received: May 13, 2008
Last updated: August 26, 2014
Last verified: August 2014
  Purpose

This study will measure the function of a protein called P-glycoprotein (P-gp), which is found at the blood-brain barrier, a membrane that normally prevents toxic material from entering the brain. Impaired P-gp function may allow toxins to enter the brain and cause some people to develop certain brain diseases.

Healthy subjects and people with Alzheimer s disease, Parkinson s disease or frontotemporal dementia who are 35 years of age or older and in overall good health may be eligible for this study.

Participants undergo the following procedures during three outpatient visits to the NIH Clinical Center:

  • Medical history, psychological evaluation, physical examination and blood and urine tests, including tests for illegal and addictive drugs.
  • PET scan: This test uses small amounts of a radioactive chemical called a tracer that labels active areas of the brain so the activity can be seen with a special camera. Before starting the scan, a catheter (plastic tube) is placed in a vein in the arm to inject the tracer. The subject lies on the scanner bed, with a special mask fitted to the head and attached to the bed to help keep the head still during the scan so the images obtained are clear. A brief initial scan is done to calibrate the scanner. Then, a radioactive tracer called [(15)O]H(2)O is injected into the catheter and the PET camera takes pictures of blood flow to the brain for about 60 seconds. Next, another tracer, [(11)C]dLop, is injected into the catheter and pictures are taken for about 2 hours to determine how much of this tracer is allowed to enter the brain.
  • Magnetic resonance imaging (MRI): This procedure is done within 1 year (before or after) the PET scan. MRI uses a magnetic field and radio waves to produce images of the brain. For this procedure, the patient lies on a table that can slide in and out of the scanner (a tube-like device), wearing earplugs to muffle loud knocking and thumping sounds that occur during the scan.

Condition
Alzheimer Disease
Parkinson Disease
Frontotemporal Lobar Degeneration

Study Type: Observational
Study Design: Time Perspective: Prospective
Official Title: Measurement of P-Glycoprotein Function in Alzheimer Disease, Parkinson Disease, and Frontotemporal Dementia Using Positron Emission Tomography

Resource links provided by NLM:


Further study details as provided by National Institutes of Health Clinical Center (CC):

Primary Outcome Measures:
  • P-gp function in AD, PD, and FTD patients and in healthy volunteers. P-gp function will be determined by calculating the brain uptake of [11C]dLop

Secondary Outcome Measures:
  • Comparing P-gp function with the severity of disease

Enrollment: 20
Study Start Date: May 2008
Estimated Study Completion Date: August 2014
Detailed Description:

Objective

Alzheimer disease (AD), Parkinson disease (PD), and frontotemporal dementia (FTD) are associated with the accumulation of neurotoxic material in the brain. Potentially toxic material is normally restricted from the brain by P-glycoprotein, a transporter protein expressed by endothelial cells at the blood-brain barrier. Disruption of the blood-brain barrier has been reported in animal models of AD, PD, and FTD, and specific dysfunction of P-gp has been linked to AD and PD pathology. Therefore, P-gp may be protective against certain neurodegenerative diseases, and P-gp dysfunction may be a risk factor for developing AD, PD, or FTD.

Positron emission tomography (PET) imaging can measure P-gp function. If P-gp function is abnormal, a radiolabeled P-gp substrate will cross the blood-brain barrier and enter the brain. Intact P-gp function, on the other hand, will prevent the substrate from entering the brain. If P-gp dysfunction is a risk factor for developing AD, PD, or FTD, then patients with these diseases should have more radiolabeled substrate in the brain than healthy controls.

We have developed a novel radioligand, [(11)C]N-desmethyl-loperamide [(11)C]dLop), which is a P-gp substrate. Our goal is to use PET imaging with [(11)C]dLop to see if P-gp function is reduced in AD, PD, and FTD.

Study population

In this protocol, we wish to evaluate 15 patients with AD, 15 patients with PD, 15 patients with FTD, and 15 healthy volunteers.

Design

Subjects will undergo screening with a history, physical exam, ECG, and blood and urine laboratory testing. Subjects will receive a dedicated brain PET with [(11)C]dLop and a brain MRI. Since [11C]dLop uptake is influenced by blood flow, a [(15)O]H2O PET scan will be performed to determine flow to the brain.

Outcome measures

Our outcome measure will be the amount of [(11)C]dLop uptake in the brain in AD, PD, and FTD patients and in healthy controls. Brain uptake will be measured as the percent standardized uptake value (%SUV). Percent SUV reflects the measured brain radioactivity after [(11)C]dLop injection, corrected for patient weight and the injected dose of [(11)C]dLop. As an exploratory outcome measure, we also will correct brain uptake for cerebral blood flow. Blood flow will be determined using [(15)O]H2O PET.

  Eligibility

Ages Eligible for Study:   35 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria
  • INCLUSION CRITERIA:
  • Patients with the diagnosis of probable Alzheimer disease, Parkinson disease, or frontotemporal dementia. All patients must either meet capacity criteria to consent to research, or be able to assign a surrogate decision-maker who is able to consent to research on the subject s behalf.
  • Healthy volunteers.

EXCLUSION CRITERIA:

  • Current psychiatric disease, substance abuse or severe systemic disease based on history and physical exam.
  • Laboratory tests with clinically significant abnormalities.
  • Subjects on blood-thinning medications, having coagulation disorders, or clinically significant abnormal blood clotting test (PT/PTT).
  • Prior participation in other research protocols or clinical care in the last year such that radiation exposure, including that from this protocol, would exceed the guidelines set by the Radiation Safety Committee (RSC).
  • Pregnancy or breast feeding.
  • Positive result on urine screen for illicit drugs.
  • Subjects who cannot lie on their back for extended periods of time.
  • History of neurological disease other than Alzheimer disease, Parkinson disease, or frontotemporal dementia.
  • Subjects who have a cardiac pacemaker or metal in their body.
  • Subjects taking cyclosporine A.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00677885

Locations
United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, United States, 20892
Sponsors and Collaborators
Investigators
Principal Investigator: William C Kreisl, M.D. National Institute of Mental Health (NIMH)
  More Information

Publications:
ClinicalTrials.gov Identifier: NCT00677885     History of Changes
Other Study ID Numbers: 080124, 08-M-0124
Study First Received: May 13, 2008
Last Updated: August 26, 2014
Health Authority: United States: Federal Government

Keywords provided by National Institutes of Health Clinical Center (CC):
Alzheimer Disease
Parkinson's Disease
Frontotemporal Dementia
PET Imaging
AD
Parkinson Disease
PD

Additional relevant MeSH terms:
Parkinson Disease
Alzheimer Disease
Frontotemporal Dementia
Aphasia, Primary Progressive
Pick Disease of the Brain
Frontotemporal Lobar Degeneration
Parkinsonian Disorders
Basal Ganglia Diseases
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Movement Disorders
Neurodegenerative Diseases
Dementia
Tauopathies
Delirium, Dementia, Amnestic, Cognitive Disorders
Mental Disorders
TDP-43 Proteinopathies
Proteostasis Deficiencies
Metabolic Diseases
Aphasia
Speech Disorders
Language Disorders
Communication Disorders
Neurobehavioral Manifestations
Neurologic Manifestations
Signs and Symptoms

ClinicalTrials.gov processed this record on September 30, 2014