CNS and Plasma Amyloid-Beta Kinetics in Alzheimer's Disease
| Status: | Completed |
|---|---|
| Conditions: | Alzheimer Disease, Hematology |
| Therapuetic Areas: | Hematology, Neurology |
| Healthy: | No |
| Age Range: | 60 - Any |
| Updated: | 12/7/2017 |
| Start Date: | December 2013 |
| End Date: | July 2017 |
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.
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.
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.
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.
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)
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