Human CNS Tau Kinetics in Tauopathies (TANGLES)

The goal of this study is to characterize tau kinetics and tau aggregation in the human CNS and to test the hypothesis that tau kinetics are altered (i.e. increased production, decreased clearance, and increased aggregation rate) in tauopathies.

Study Overview

• Status: Completed
• Conditions: Progressive Supranuclear Palsy (PSP); Corticobasal Degeneration (CBD); Frontotemporal Dementia (FTD MAPT Mutation)
• Intervention / Treatment: Other: 13C6 Leucine

Detailed Description

Tauopathies are neurodegenerative diseases with tau pathology. These tauopathies are the most common pathology in neurodegenerative diseases, and they are reaching epidemic proportions. The rates of tau kinetics are central to understanding normal and abnormal processing and production and clearance of tau kinetics in humans to help understand the causes of tauopathy and evaluate tau-targeted therapeutics.

This study will utilize the Stable Isotope Labeling Kinetics (SILK) method to elucidate tau kinetics in vivo in the human central nervous system (CNS) and its alteration in tauopathies. A total of ~34 participants from 3 different neurodegenerative diseases: Frontotemporal Dementia (FTD), Corticobasal Degeneration (CBD), and Progressive Supranuclear Palsy (PSP), will be invited to enroll in the study.

Participants will be labeled with stable isotopes via 16hr intravenous infusion and CSF samples collected during subsequent lumbar puncture visits over ~120 days. CSF will be analyzed over time for the quantitation of labeled tau.

• Study Type: Observational
• Enrollment (Actual): 27

Contacts and Locations

Study Locations

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

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Progressive Supranuclear Palsy (PSP): N=12

Corticobasal Degeneration (CBD): N=8

Frontotemporal Dementia (FTD): MAPT: Family members with or at-risk of tau mutations (e.g. P301L) N=12

Description

Inclusion Criteria:

• Diagnosed with PSP, CBD, or FTD MAPT

Exclusion Criteria:

• Clotting disorder
• Active anticoagulation therapy
• Active infection
• Meningitis
• Recent syncope
• Current 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: Prospective

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Progressive Supranuclear Palsy (PSP); N=12 Age: 18 and older Recruited participants will be given 13C6 Leucine through intravenous infusion (4mg/kg/hr for 16hrs), and CSF will be collected five times over 120 days (on approximately days 1-4, 5-10, 11-20, 21-60 and 61-120) after labeling.	Other: 13C6 Leucine; Recruited participants will be given 13C6-labeled leucine through intravenous infusion (4mg/kg/hr for 16hrs)
Corticobasal Degeneration (CBD); N=8 Age: 18 and older Recruited participants will be given 13C6 Leucine through intravenous infusion (4mg/kg/hr for 16hrs), and CSF will be collected five times over 120 days (on approximately days 1-4, 5-10, 11-20, 21-60 and 61-120) after labeling.	Other: 13C6 Leucine; Recruited participants will be given 13C6-labeled leucine through intravenous infusion (4mg/kg/hr for 16hrs)
Frontotemporal Dementia: MAPT; N=12 Family members with or at-risk of tau mutations (e.g. P301L) Age: 18 and older Recruited participants will be given 13C6 Leucine through intravenous infusion (4mg/kg/hr for 16hrs), and CSF will be collected five times over 120 days (on approximately days 1-4, 5-10, 11-20, 21-60 and 61-120) after labeling.	Other: 13C6 Leucine; Recruited participants will be given 13C6-labeled leucine through intravenous infusion (4mg/kg/hr for 16hrs)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Tau Fractional Turnover Rate (FTR)	Calculated by using CSF tau labeling and plasma free leucine.	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
CSF Tau Absolute Concentration	Measured using labeled and unlabeled tau protein isoforms that will be immunoprecipitated and analyzed by mass spectrometry.	6 months
Tau Production Rate	Measured by FTR multiplied by CSF tau concentration.	6 months

Collaborators and Investigators

• Sponsor: Washington University School of Medicine
• Collaborators: Association of Frontotemporal Degeneration; Tau Consortium
• Investigators: Principal Investigator: Randall Bateman, MD, Washington University in Saint Louis Medical School; Principal Investigator: Nupur Ghoshal, MD, PhD, Washington University in Saint Louis Medical School

Study record dates

Study Major Dates

• Study Start (Actual): August 21, 2017
• Primary Completion (Actual): March 4, 2022
• Study Completion (Actual): March 4, 2022

Study Registration Dates

• First Submitted: March 12, 2018
• First Submitted That Met QC Criteria: May 31, 2018
• First Posted (Actual): June 4, 2018

Study Record Updates

• Last Update Posted (Actual): April 13, 2022
• Last Update Submitted That Met QC Criteria: April 12, 2022
• Last Verified: April 1, 2022

More Information

Terms related to this study

• Keywords: Tauopathies
• Additional Relevant MeSH Terms: Mental Disorders; Metabolic Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Eye Diseases; Neurologic Manifestations; Neurobehavioral Manifestations; Neurocognitive Disorders; Basal Ganglia Diseases; Movement Disorders; Neurodegenerative Diseases; TDP-43 Proteinopathies; Proteostasis Deficiencies; Dementia; Cranial Nerve Diseases; Ocular Motility Disorders; Language Disorders; Communication Disorders; Paralysis; Speech Disorders; Frontotemporal Lobar Degeneration; Ophthalmoplegia; Aphasia; Frontotemporal Dementia; Aphasia, Primary Progressive; Pick Disease of the Brain; Supranuclear Palsy, Progressive; Tauopathies
• Other Study ID Numbers: 201703052

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided
• IPD Plan Description: Undecided at this time.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No