CNS and Plasma Amyloid-Beta Kinetics in Alzheimer's Disease

CNS and Plasma Amyloid-Beta Kinetics in Alzheimers's Disease; A Blood Isotope Labeled Amyloid-beta Test for Alzheimer's Disease.

Alzheimer's disease (AD) is the most common cause of dementia and currently has no disease modifying treatments or simple accurate diagnostic tests. The goal of this project is to study how amyloid-beta (a protein thought to cause AD) is made, transported and cleared in the human body. Better understanding of these processes may lead to improved understanding of AD, earlier diagnosis and a way to evaluate treatment.

Study Overview

• Status: Completed
• Conditions: Alzheimer's Disease

Detailed Description

The overall goal is to determine the changes that occur in amyloid-beta (Aβ) metabolism in Alzheimer's disease (AD) and model the production, transport, metabolism and clearance of Aβ in the human central nervous system (CNS) and periphery to improve clinical trial designs and also possibly develop an AD blood test.

Clearance of brain Aβ occurs by enzymatic digestion (e.g. Insulin Degrading Enzyme, Neprilysin, etc.), cellular uptake and breakdown, transport across the blood-brain-barrier, and transport from the brain to cerebrospinal fluid (CSF) and then to blood. However, the relationship between CNS Aβ and blood Aβ is not known in humans and only partly understood in other animals. The goal is to determine the kinetics of Aβ in the CNS and blood to test the hypothesis that altered Aβ kinetics in the CNS in AD is associated with altered blood Aβ labeling kinetics. Understanding blood and CSF Aβ kinetics will contribute to a better understanding of Aβ production, transport, and breakdown within and between the brain, CSF and blood compartments. These fundamental measurements of Aβ kinetics in AD will help determine the effects of peripheral Aβ metabolism on pathophysiologic changes in AD. This information will provide key insights into whole body Aβ metabolism and will be useful for understanding the causes of AD. Further, these results may lead to a specific blood biomarker for AD.

Aim 1. To determine blood Aβ isoform SILK (stable isotope-linked kinetics) using existing steady state infusion labeled blood samples from amyloid positive and amyloid negative control participants. Blood Aβ kinetics will be compared to CSF Aβ kinetics and combined utilizing multi-compartment and structural models to determine the direction and magnitude of transport and breakdown.

Current labeling methods employ a primed continuous infusion which labels Aβ to near steady-state. In order to provide additional kinetic information on Aβ kinetics and potentially better distinguish AD from controls, an alternative pulse labeling protocol is proposed. In addition to providing clearer information on Aβ transport and clearance, the simplified labeling method makes blood Aβ kinetics feasible as a clinical test for treatment trials or as a diagnostic test.

Aim 2. To perform pulse bolus labeling in amyloid positive and amyloid negative controls and measure CSF Aβ isoform kinetics and blood Aβ isoform kinetics. Participants will be recruited to complete a pulse labeling study. Results from Aim 2 will be incorporated into complimentary models with results from Aim 1 and ongoing studies to provide measures of Aβ production, transport, and breakdown within and between the brain, CSF and blood compartments.

Approach: Based on preliminary data and published studies, the hypothesis will be tested that blood Aβ isoform kinetics are disrupted in AD and to model the Aβ production, transport and clearance between the brain and periphery. The data from these studies will be useful to model the production, transport and breakdown of Aβ throughout the human body.

Results of these aims will be utilized in complimentary modeling approaches and combined with the results of prior studies to provide a comprehensive model of in vivo Aβ kinetics in both the human CNS and periphery. The data and models will be able to confirm and exclude current hypotheses of human Aβ metabolism. The goals of the aims are to determine the CNS Aβ isoform kinetics with a pulse labeling protocol (Aim 1), and to determine the peripheral blood Aβ isoform kinetics with a pulse labeling protocol (Aim 2).

Experimental Design: A pulse labeling protocol with twenty participants was completed to simplify labeling. Pulse labeling experiments provided additional kinetics results to determine Aβ kinetic models. Of the next sixty participants most will be re-enrolled that have completed prior intravenous steady-state labeling Aβ SILK studies. All participants will have had a PET/PIB scan completed for fibrillar amyloid deposition measurements or CSF Aβ42 concentration measurements.

Clinical Study: A single pulse dose of leucine will be given at the beginning of the study and blood and/or CSF will be collected for 24-36 hours.

Data Analysis: We will compare the pulse labeling blood Aβ SILK results of the amyloid positive vs. amyloid negative control group for Aβ38, Aβ40, Aβ42, and ratios of isoforms vs. tests of amyloidosis such as PET/PIB scan and/or CSF Aβ42 concentration.

• Study Type: Observational
• Enrollment (Actual): 58

Contacts and Locations

Study Locations

• United States
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University in St. Louis

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 60 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Adults from the Alzheimer's Disease Research Center and Memory and Aging Project at Washington University.

Description

Inclusion Criteria:

• Member of the Memory and Aging Project at Washington University
• Clinical Dementia Rating (CDR) and PET/ PIB scores
• Age 60 or greater

Exclusion Criteria:

• Clotting disorder
• Active anticoagulation therapy
• Active infection
• Meningitis
• Recent syncope
• Currently on experimental treatment targeting Aβ or medications thought to influence Aβ production or clearance rates (benzodiazepines, muscarinic agents, or anti-epileptics)

Study Plan

How is the study designed?

Design Details

• Observational Models: Case-Control
• Time Perspectives: Cross-Sectional

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort
Amyloid positive (Amyloidosis); Amyloidosis defined by positive Positive emission tomography (PET)/Pittsburg Compound B (PIB) score, or low CSF Aβ42 concentration.
Amyloid negative (Control); Amyloid negative defined by negative Positive emission tomography (PET)/Pittsburg Compound B (PIB) score or high/normal CSF Aβ42 concentration .

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Analysis of SILK blood and CSF Aβ isoforms	Analysis of SILK blood and CSF Aβ isoforms will be performed. The pulse labeling blood Aβ SILK results of the amyloid positive group will be compared with the control group for Aβ38, Aβ40, Aβ42, and ratios of isoforms vs. tests of amyloidosis such as PET/PIB scan and/or CSF Aβ42 concentration.	Sample collection 24 - 96 hours post labeling

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Age	SILK blood and CSF Aβ isoforms analyzed by clinical diagnosis (AD vs. controls) and Age.	Sample collection 24-96 hours post labeling
CSF tau/ptau	SILK blood and CSF Aβ isoforms analyzed by clinical diagnosis (AD vs. controls) for CSF tau/ptau.	Sample collection 24-96 hours post labeling
PET/Fluoro-D-glucose (FDG) scan findings.	SILK blood and CSF Aβ isoforms analyzed by clinical diagnosis (AD vs. controls) and by PET/Fluoro-D-glucose (FDG) scan findings.	Sample collection 24-96 hours post labeling
ApoE	SILK blood and CSF Aβ isoforms analyzed by clinical diagnosis (AD vs. controls) for Apolipoprotein E (ApoE).	Sample collection 24-96 hours post labeling
Mutation status	SILK blood and CSF Aβ isoforms analyzed by clinical diagnosis (AD vs. controls) and mutation status for AD.	Sample collection 24-96 hours post labeling
Cognitive measures	SILK blood and CSF Aβ isoforms analyzed by clinical diagnosis (AD vs. controls) and cognitive measures.	Sample collection 24-96 hours post labeling
Clinical measures	SILK blood and CSF Aβ isoforms analyzed by clinical diagnosis (AD vs. controls) and clinical measures.	Sample collection 24-96 hours post labeling
MRI	SILK blood and CSF Aβ isoforms analyzed by clinical diagnosis (AD vs. controls) and by Magnetic resonance imaging (MRI) findings.	Sample collection 24-96 hours post labeling

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
novel CSF biomarkers	SILK blood and CSF Aβ isoforms analyzed by clinical diagnosis (AD vs. controls) for novel CSF biomarkers.	Sample collection 24-96 hours post labeling
novel imaging protocols	SILK blood and CSF Aβ isoforms analyzed by clinical diagnosis (AD vs. controls) and by novel imaging protocols.	Sample collection 24-96 hours post labeling

Collaborators and Investigators

• Sponsor: Washington University School of Medicine
• Collaborators: National Institute of Neurological Disorders and Stroke (NINDS)
• Investigators: Principal Investigator: Randall J Bateman, MD, Washington University School of Medicine

Publications and helpful links

General Publications

• Mawuenyega KG, Sigurdson W, Ovod V, Munsell L, Kasten T, Morris JC, Yarasheski KE, Bateman RJ. Decreased clearance of CNS beta-amyloid in Alzheimer's disease. Science. 2010 Dec 24;330(6012):1774. doi: 10.1126/science.1197623. Epub 2010 Dec 9.
• Potter R, Patterson BW, Elbert DL, Ovod V, Kasten T, Sigurdson W, Mawuenyega K, Blazey T, Goate A, Chott R, Yarasheski KE, Holtzman DM, Morris JC, Benzinger TL, Bateman RJ. Increased in vivo amyloid-beta42 production, exchange, and loss in presenilin mutation carriers. Sci Transl Med. 2013 Jun 12;5(189):189ra77. doi: 10.1126/scitranslmed.3005615.

Study record dates

Study Major Dates

• Study Start (Actual): December 1, 2013
• Primary Completion (Actual): July 1, 2017
• Study Completion (Actual): July 1, 2017

Study Registration Dates

• First Submitted: December 19, 2013
• First Submitted That Met QC Criteria: December 19, 2013
• First Posted (Estimate): December 27, 2013

Study Record Updates

• Last Update Posted (Actual): December 5, 2017
• Last Update Submitted That Met QC Criteria: December 1, 2017
• Last Verified: December 1, 2017

More Information

Terms related to this study

• Keywords: dementia; Alzheimer's Disease; biomarker; Alzheimer's; Aβ; ABeta; ABeta kinetics; amyloid beta; PET/PIB
• Additional Relevant MeSH Terms: Mental Disorders; Metabolic Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurocognitive Disorders; Neurodegenerative Diseases; Proteostasis Deficiencies; Dementia; Tauopathies; Amyloidosis; Alzheimer Disease
• Other Study ID Numbers: In Vivo metabolism of ABeta; R01NS065667 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No
• IPD Plan Description: No plan to share IPD at this time