Human CNS Tau Kinetics in Tauopathies

Completed

• Conditions: Frontotemporal Dementia (FTD MAPT Mutation); Progressive Supranuclear Palsy (PSP); Corticobasal Degeneration (CBD)
• Interventions: Other: 13C6 Leucine

• Registration Number: NCT03545126
• Lead Sponsor: Washington University School of Medicine

Brief Summary

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.

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 Timeline

• Study Start: 2017-08-21
• Study First Submitted: 2018-03-12
• Study First Submitted QC: 2018-05-31
• Study First Posted: 2018-06-04
• Primary Completion: 2022-03-04
• Study Completion: 2022-03-04
• Status Verified: 2022-04
• Last Update Submitted: 2022-04-12
• Last Update Posted: 2022-04-13

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 27

Inclusion Criteria

• Diagnosed with PSP, CBD, or FTD MAPT

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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)

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Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Arm && Interventions

Group	Intervention	Description
Corticobasal Degeneration (CBD)	13C6 Leucine	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.
Frontotemporal Dementia: MAPT	13C6 Leucine	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.
Progressive Supranuclear Palsy (PSP)	13C6 Leucine	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.

Primary Outcome Measures

Name	Time	Method
Tau Fractional Turnover Rate (FTR)	6 months	Calculated by using CSF tau labeling and plasma free leucine.

Secondary Outcome Measures

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

Trial Locations

Locations (1)

Washington University in St. Louis School of Medicine; 🇺🇸 Saint Louis, Missouri, United States