CNS Tau Kinetics in Healthy Aging and Alzheimer's Disease

The goal of this study is to examine how tau works in the Human Central Nervous System (CNS)and to test the hypothesis, that tau is altered (i.e. increased production, decreased clearance, and increased collection rate) with age, and in diseases caused by the disruption of how tau usually works. We will first test this hypothesis in AD and then test and compare other tau diseases in future studies. We have recently developed a novel approach to measure tau in the human CNS. We propose to utilize this approach to address fundamental questions of human tau production and metabolism in Alzheimer's disease. Researchers have designed this study to determine how long tau stays in the body. It involves labeling or marking tau with a special type of an essential amino acid called leucine. Our bodies naturally get leucine from the foods that we eat.

In this study, the participant will either be given labeled leucine through intravenous infusion, or be given labeled leucine in a drink. The researchers think that it would be more convenient for the participant if the study was done giving the leucine by infusion but this method has not been tested with tau. The first part of the study is to test the infusion method and find the optimal infusion rate and length of time to hopefully see tau. If the method cannot be confirmed with the young normal control group the study will move on to using the oral method of labeling. This has been proven to work but it will be more burdensome for the participants. The leucine is a stable form of carbon found in nature and has no side effects but it will stick to certain proteins such as tau making the tau "visible" to researchers. Once labeled, the researchers will take samples of Cerebral Spinal Fluid (CSF) at different time points and determine how long the tau stays in the system. This amount of time is called the "half-life". Knowing the half-life of tau will help researchers to develop clinical trials that target tau and future therapeutic interventions for AD.

The first type of labeling is Intravenous Infusion of Leucine. After successful screening, the subject would come to the CARS at 07:00 AM, (fasting from 10:00 PM the night before), and have an intravenous catheter placed. The researchers do not know exactly how much Leucine it will take to successfully label Tau so that they can see it. The first studies will be with Young Normal controls ages 18 and older. The researcher will test the following amounts of leucine; Leucine infusion for 24 hours at a rate of 4 mg/kg/hour. The researchers will process the samples immediately. If tau is visible at this amount a second participant will receive a lesser infusion time, leucine infusion for 16 hours at a rate of 4mg/kg/hour. The researchers will process the samples immediately, if tau is visible at this amount a third participant will receive a lesser amount of leucine to label tau. Leucine infusion at a rate of 2/mg/kg/hour for 24 hours. The samples will be tested and if the tau is seen at this amount then a lesser amount of infusion time will be tried. The leucine infusion will be done at at rate of 2/mg/kg/hour for 16 hours. This would be the goal of the study to infuse the least amount of leucine for the least amount of time.

All meals are prepared by the Research Kitchen. When receiving leucine the participant has to have their meals controlled for the natural leucine found in our diets. The participant receives three meals and three snacks in the 24 hours and then a BJC cafeteria breakfast after their first lumbar puncture.

Once the amount and time of leucine infusion is optimal more Young Normal Controls will repeat the infusion study for confirmation. Each participant will complete a total of 5 Lumbar Punctures over time.