P-glycoprotein Function in Brain Diseases

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.